Molecules 26 01132

molecules
Review
Advances and Perspectives in the Management of
Varicella-Zoster Virus Infections
Graciela Andrei * and Robert Snoeck
Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, KU Leuven, 3000 Leuven,
Belgium; robert.snoeck@kuleuven.be
* Correspondence: graciela.andrei@kuleuven.be; Tel.: +32-16-32-19-51
Abstract: Varicella-zoster virus (VZV), a common and ubiquitous human-restricted pathogen, causes
a primary infection (varicella or chickenpox) followed by establishment of latency in sensory ganglia.
The virus can reactivate, causing herpes zoster (HZ, shingles) and leading to significant morbidity
but rarely mortality, although in immunocompromised hosts, VZV can cause severe disseminated
and occasionally fatal disease. We discuss VZV diseases and the decrease in their incidence due to
the introduction of live-attenuated vaccines to prevent varicella or HZ. We also focus on acyclovir,
valacyclovir, and famciclovir (FDA approved drugs to treat VZV infections), brivudine (used in
some European countries) and amenamevir (a helicase-primase inhibitor, approved in Japan) that
augur the beginning of a new era of anti-VZV therapy. Valnivudine hydrochloride (FV-100) and
valomaciclovir stearate (in advanced stage of development) and several new molecules potentially
good as anti-VZV candidates described during the last year are examined. We reflect on the role
of antiviral agents in the treatment of VZV-associated diseases, as a large percentage of the at-risk

population is not immunized, and on the limitations of currently FDA-approved anti-VZV drugs.
Their low efficacy in controlling HZ pain and post-herpetic neuralgia development, and the need of
Citation: Andrei, G.; Snoeck, R. multiple dosing regimens requiring daily dose adaptation for patients with renal failure urges the
Advances and Perspectives in the development of novel anti-VZV drugs.
Management of Varicella-Zoster
Virus Infections. Molecules 2021, 26, Keywords: varicella-zoster virus (VZV); chickenpox; HZ; shingles; nucleoside analogues; helicase-
1132. https://doi.org/10.3390/ primase inhibitors; valnivudine hydrochloride (FV-100); valomaciclovir stearate; amenamevir; anti-
molecules26041132 VZV drugs
Academic Editors: Libor Grubhoffer

and Masanori Baba
1. Introduction
Received: 12 January 2021
Accepted: 12 February 2021
Varicella-zoster virus (VZV), also known as human herpesvirus 3 (HHV-3) has a
Published: 20 February 2021
double-stranded DNA genome of 125 kb, encoding for approximately 71 open read-
ing frames (ORFs). The herpesvirus family includes three subfamilies, α, β, and γ-
Publisher’s Note: MDPI stays neutral
herpesvirinae. VZV together with herpes simplex virus 1 and 2 (HSV-1 and HSV-2) belong
with regard to jurisdictional claims in
to the α-herpesvirinae, characterized by establishment of latency in neurons.
published maps and institutional affil- VZV is the causative agent of chickenpox (varicella), a common infantile illness.
iations. Like all herpesviruses, VZV undergoes a lifelong latent state following primary infection.
During latency, the viral DNA persists in the dorsal root ganglia and cranial root ganglia.
VZV reactivation produces skin lesions characteristic of herpes zoster (shingles), causing
significant morbidity, but rarely mortality [1]. Herpes zoster (HZ) is characterized by a
Copyright: © 2021 by the authors.
localized rash in a unilateral, dermatomal distribution and is often associated with severe
Licensee MDPI, Basel, Switzerland.
neuropathic pain.
This article is an open access article
VZV is highly infectious and enters the body via the respiratory tract, followed by
distributed under the terms and rapid spread from the pharyngeal lymphoid tissue to circulating T lymphocytes [2]. After
conditions of the Creative Commons 10–21 days, the virus arrives at the skin, producing the typical vesicular rash characteristic
Attribution (CC BY) license (https:// of varicella. In most individuals, VZV infection results in lifelong immunity. During VZV
creativecommons.org/licenses/by/ reactivation, the virus is transported along microtubules within sensory axons to infect
4.0/). epithelial cells, usually without viremia. This gives a skin rash within the dermatome
Molecules 2021, 26, 1132. https://doi.org/10.3390/molecules26041132 https://www.mdpi.com/journal/molecules

Molecules 2021, 26, 1132 2 of 34
innervated by a single sensory nerve [the trigeminal (cranial nerve), cervical and thoracic
sensory nerves are the most common nerves involved in VZV reactivation]. The virus can
also be transmitted by fomites from varicella and shingles skin lesions. Reactivation from
latency occurs when there is a weakening in cell-mediated immunity (CMI) as a natural
consequence of aging since VZV-specific T cells lose their ability to proliferate with age
or with immune suppression. Risks factors for HZ include older age, CMI dysfunction,
diabetes, female gender, genetic susceptibility, physical trauma, recent psychological stress,
and white race [2].
The narrow host range (VZV infection is highly restricted to humans) coupled with
the highly cell-associated nature of the virus, has hampered the development of a reliable
animal model that mimics VZV diseases in human, thereby hindering VZV pathogenesis
studies.
2. Clinical Characteristics of VZV Infections

Primary VZV infection generally occurs in childhood and is usually mild but compli-
cations can occur in adults and in immunocompromised patients. Disseminated varicella
infections with multi-organ failure have been reported in both immunocompetent [3–5]
and immunocompromised patients [5–7]. Although VZV reactivation leading to HZ may
occur at any age, the highest incidence is seen in the elderly and among immunocompro-
mised individuals (HIV/AIDS individuals or patients suffering from malignancies, organ
or hematopoietic stem cell transplant (HSCT) recipients or persons receiving high-dose
corticosteroid therapy). Age-related impaired CMI facilitates VZV reactivation from latency.
HZ affects up to 25% of human beings during their lifetime, with 50% of persons being
aged 80 years or more [8]. HZ is rarely life threatening but it is associated with a number of
acute syndromes, including a vesicular rash and pain. It can lead to prolonged pain, known
as post-herpetic neuralgia (PHN), a debilitating condition, which can be very difficult to
manage, mainly in the elderly where the disease tends to be more serious [9,10]. PHN is
associated with a loss of physical function, encompassing fatigue, anorexia, weight loss,
reduced mobility, physical inactivity, sleep disturbance (especially insomnia) resulting
in a loss of social contact. A positive correlation between enhanced severity of pain and
higher interference with daily activities was reported [9]. Ophthalmological manifestations
of VZV may also occur. About 10–15% of HZ cases are subtyped as HZ ophthalmicus
(HZO), occurring when the virus is reactivated in the ophthalmic division of the trigeminal
nerve [11]. Approximately 50% of individuals with HZO develop ophthalmic compli-
cations [12]. Chronic ocular inflammation, loss of vision, and debilitating pain can be
permanent sequelae of HZO.
Similar to other α-herpesviruses, VZV is able to infect the central nervous system
(CNS) to cause encephalitis, either as a complication of varicella or HZ, but also in the
absence of rash. About 50% of VZV encephalitis cases occur in individuals with immuno-
suppressive conditions, in whom viral reactivation is more common. A high viral diversity
and mixed infections with different clades in the cerebrospinal fluid (CSF) from patients
with VZV encephalitis, which can be explained by viral reactivation from multiple neurons,
may contribute to the pathogenesis of VZV encephalitis [13].
VZV infections among immunocompromised patients can be more severe, of longer
duration than in immunocompetent individuals and may have unusual clinical presenta-
tion with multidermal involvement and hyperkeratotic skin lesions [14,15]. VZV can be
associated with severe acute retinal necrosis (ARN), a disease with poor prognosis; typically
occurring in immunocompetent individuals though it can also occur in immunocompro-
mised patients [16,17]. Unlike VZV necrotizing retinitis, progressive outer retinal necrosis
(PORN), a form of VZV chorioretinitis, is found mostly in severely compromised people
though, exceptionally, some cases of PORN have been described in immunocompetent
persons [18–21]. Treatment strategies for PORN are rather unsuccessful and the disease
can evolve fast leading to blindness within a few days or weeks.
Molecules 2021, 26, 1132 3 of 34
3. Vaccination Strategies and Post-Exposure Prophylaxis

Varivax® (the live-attenuated vaccine for varicella from Merck Sharp & Dohme Corp.,
Table 1), which is based on the VZV attenuated Oka strain (vaccine Oka, vOka), was
licensed in United States in 1995 for children aged 12 to 18 months, leading to a substantial
drop in the incidence of varicella. GlaxoSmithKline also developed and launched a live
vOka preparation (Varilrix® ), for immunization against VZV infections in 1998. To prevent
mild breakthrough infections among vaccinated children following a single dose of vOka,
a recommendation for a 2-dose schedule was given in 2006 to improve immunity to VZV.
The live-attenuated heterogeneous vaccine preparation vOka is used routinely in many
countries worldwide, which resulted in a significant decline in the incidence of varicella
disease, with a decrease risk of developing zoster [22]. The varicella vaccine has a very
good safety profile. Only less than 5% vaccine recipients can develop a papular or vesicular
rash, usually at the site of infection within 6 weeks following vaccination. Vaccinated
individuals have minimum risk for transmitting vOka to contact persons and transmission
occurs only in the presence of a rash [23]. Generalized varicella-like rashes can develop
rarely within 14 days after vaccination and are due to wild-type VZV incidentally acquired
soon after vaccination. vOka also establishes latent infection in vaccine recipients and may
very rarely reactivate to cause HZ. Vaccine-related HZ occurs less frequently and is less
severe than wild-type VZV reactivation and always manifests as HZ of one dermatome.
Like most live attenuated viral vaccines, the emergence of vaccine-wild type recombinant
strains can occur. VZV frequently undergoes genetic recombination, and the vaccine strains
have already been found in recombination events with the wild-type [24].
Table 1. Vaccines available against varicella-zoster virus. Comparative characteristics of the available varicella zoster and
herpes zoster vaccines.
Varicella Vaccine Herpes Zoster Vaccine

Name Varivax® & Varilrix® Zostavax® Shingrix®
Year of FDA
1995 2006 2018
licensure
Merck (Varivax® )
Manufacturer Merck GSK
GSK (Varilrix® )
Inactivated; Recombinant
Type Life-attenuated viral vaccine Life-attenuated viral vaccine
subunit
Vaccine components Oka strain (1350 PFU) Oka strain (19,400 PFU) VZV glycoprotein E (gE)
• Routine 2-dose vaccination 1st
dose at 12–15 months old 2nd
dose at 4–6 years old
Number of doses • 2nd dose catch-up vaccination ≥3
1 dose 2 doses (2–6 months apart)
administered months after 1st dose for children
aged <13 years of age
• Adolescent & adults 2 doses 4 to 8
weeks apart
Storage Freezer Freezer Refrigerator
Diluent Sterile water Sterile water Adjuvant
0.65 mL vial for subcutaneous 0.5 mL vial for intramuscular
Dose form 0.5 mL vial for intramuscular injection
injection injection
• ≥ children 12 months • FDA approved: ≥50 • FDA approved: ≥50

• Adults without evidence of years old years old
Recommended age
immunity to varicella • CDC recommendation: • CDC recommendation:
≥60 years old ≥60 years old
Molecules 2021, 26, 1132 4 of 34
Table 1. Cont.
Varicella Vaccine Herpes Zoster Vaccine

Name Varivax® & Varilrix® Zostavax® Shingrix®
• Shingles prevention Age
• Shingles prevention Age
50–59: 69% Age 60–69:
50–59: 97.2% Age 60–69:
64% Age 70–79: 41% Age
About 98% protection in children and 96.6% Age 70–79: 91.3%
≥80: 18% efficacy
Efficacy about 75% protection in teenagers and Age ≥80: 91.4%
• PHN protection Age
adults • PHN protection Age ≥
60–69: 51% Age 70–79:
50: 91.2% Age ≥ 70:
64% Age ≥80: 41%
88.8%
Overall: 51%
Unknown; however, long-term efficacy
studies have demonstrated continued
Immunity duration Age-dependent Age-dependent
protection up to 10 years after
vaccination
• People with a history of • Individuals with a
severe allergic reaction history of severe allergic
• Immunocompromised (primary or (e.g., anaphylaxis) to any reaction (e.g.,
acquired) patients component of the anaphylaxis) to any
• Family history of congenital vaccine component of the
immunodeficiency’s • Immunocompromised vaccine or after a
Contraindications
• Individuals with anaphylactic patients previous dose of
reaction to any component of the • Individuals with family Shingrix.
vaccine efficacy history of congenital • Pregnant and
immunodeficiency’s breastfeeding women
• Pregnant and • Persons who currently
breastfeeding women have shingles
Most commonly:
Most commonly: • Pain, redness, and Most commonly:
swelling at the
• Fever • Pain, redness, swelling,
injection site
• Pain, redness, and swelling at the warmth or itching at the
Possible side effects • Muscle pain
injection site site of injection at the
• Tiredness
• Varicella-like rash (transmission of injection site
• Headache
varicella-virus can occur) • Headache
• Shivering
• Fever
• Upset stomach
Two vaccines (Zostavax® and Shingrix® , Table 1) are currently available to boost the
CMI to VZV. Both vaccines proved to be safe and immunogenic and to reduce the incidence
of HZ and PHN. The efficacy of the life-attenuated HZ vaccine (Zostavax® ) decreases with
age at the time of vaccination and with time since vaccination. The vaccine efficacy of re-
combinant HZ vaccine (Shingrix® ) remains higher and appears to decline more slowly than
that of the life-attenuated vaccine across all age groups. Both vaccines are cost-effective
in individuals ≥50 years of age compared with no vaccination, especially among those
65–79 years of age and Shingrix appears to be more cost-effective than Zostavax® . Impor-
tantly, a live attenuated vaccine, such as Zostavax® , cannot be given to immunosuppressed
patients and this patient population is at high risk for developing HZ. In contrast, Shingrix
can be given to persons with impaired immune conditions [25].
VariZIG® (Saol Therapeutics) is a VZV immune globulin preparation available for
post-exposure prophylaxis of varicella in persons at high-risk for severe disease who lack
immunity to VZV and who are ineligible for varicella vaccine. High-risk groups encompass
immunocompromised persons (children and adults), newborns of mothers who developed
varicella just before or shortly after delivery, premature babies, children younger than one
year of age, adults without evidence of immunity and pregnant women. The time during
Molecules 2021, 26, 1132 5 of 34
which a patient may receive VariZIG® after VZV exposure has been prolonged from 4 days
to 10 days.
4. Treatment of VZV-Associated Diseases

Molecules 2021,2021,
Molecules 26, 1132
26, 2021,
1132 26, 1132 5 of 35
5 of 35
Molecules Safe and effective anti-VZV therapy considerably contributed to diminish the morbid- 5 of 35
ity and mortality associated with varicella and HZ, in particular in immunocompromised
populations. The drugs licensed for the treatment of VZV-associated disease in United
4. Treatment
4. Treatment of VZV‐Associated
4. Treatmentof VZV‐Associated
of VZV‐Associated Diseases
Diseases Diseases
States include acyclovir (ACV), its oral prodrug valacyclovir (VACV), and famciclovir
SafeSafeandand effective
Safeprodrug anti‐VZV
effective anti‐VZV
and effective therapytherapy considerably
anti‐VZV therapy considerably contributed
considerablycontributed to diminish
to diminish
contributed tothe mor‐
the
diminish mor‐ the mor‐
(FCV), the oral of penciclovir (PCV) (Table 2).
bidity andand
bidity mortality
mortality
bidity and associated
associated
mortality with varicella
with varicellaand HZ,
and in
HZ,
associated with varicella and HZ,Zovirax particular
in particular in immunocompro‐
in
in particular® immunocompro‐
in immunocompro‐
Acyclovir [ACV, 9-(2-hydroxyethoxymethyl)guanine, ], a structural analogue
misedmisedpopulations.
populations.
mised compound TheThe drugs
populations. 0 licensed
drugs drugsfor
licensed the the
for treatment
treatment of VZV‐associated
of VZV‐associated diseasedisease in disease
in
of theStates
United natural include acyclovir 2The-deoxyguanosine
(ACV),
licensed
its oral
for
(Table
prodrug
the2),treatment
is a potent
valacyclovir
of VZV‐associated
and
(VACV),selective and inhibitorinof
UnitedUnited States Statesincludeincludeacyclovir (ACV),(ACV),
acyclovir its oralitsprodrugoral valacyclovir
prodrug valacyclovir(VACV), and and
(VACV),
VZV,
famciclovir HSV-1,
famciclovir (FCV), HSV-2,
the (FCV),
(FCV), oral
the and Epstein-Barr
prodrug
oral prodrug ofprodrug virus (PCV)
penciclovir
of penciclovir (EBV) (PCV) with
(Table modest
(Table2). 2). activity against human cy-
famciclovir the oral of penciclovir (PCV) (Table 2).
tomegalovirus
Acyclovir
Acyclovir [ACV,(HCMV).
[ACV, Acyclovir and its prodrug valacyclovir
9‐(2‐hydroxyethoxymethyl)guanine,
9‐(2‐hydroxyethoxymethyl)guanine, Zovirax Zovirax ®], a ®(L-valyl
],structural
a structural ester ana‐ ofana‐acyclovir)
Acyclovir [ACV, 9‐(2‐hydroxyethoxymethyl)guanine, Zovirax ®], a structural ana‐
are
logue the
of the
logue gold
of natural
the standard
naturalcompound for prophylaxis
compound 2′‐deoxyguanosine and therapy
2′‐deoxyguanosine (Table (Table ofis2),
2), HSV a potent
is a and
potent VZV
and associated
selective
and selective in‐ in‐ diseases.
logue of the natural compound 2′‐deoxyguanosine (Table 2), is a potent and selective in‐
Acyclovir
hibitor of VZV,
hibitor isHSV‐1,
of VZV,
hibitor converted
ofHSV‐1,
VZV,HSV‐2, to and
HSV‐2,
HSV‐1, itsHSV‐2,
monophosphate
Epstein‐Barr
and Epstein‐Barr virus
and Epstein‐Barr (ACV-MP)
(EBV)
virus (EBV)withwith
virus (EBV)bymodest
modest the
with viral
activity
activity
modest thymidine
againstagainstagainst
activity kinase
human
(TK),
human cytomegalovirus
which is further
cytomegalovirus (HCMV).
phosphorylated
(HCMV). Acyclovir
Acyclovir and
by its prodrug
cellular
and its kinases
prodrug
human cytomegalovirus (HCMV). Acyclovir and its prodrug valacyclovir (L‐valyl ester valacyclovir
to (L‐valyl
ACV-triphosphate
valacyclovir (L‐valyl ester ester(ACV-TP)
of (Figure
acyclovir) 1).are
of acyclovir)
of the the
are
ACV-TP,
acyclovir) gold the
are standard
gold goldfor
standard
active
the form prophylaxis
forof
standard prophylaxis
acyclovir, andand
for prophylaxis therapy
is a therapy of therapy
competitive
and HSV
of HSV and VZV
ofand
inhibitor
HSV VZVassoci‐
and associ‐
with VZV respect
associ‐to
ated
thediseases.
ated diseases.
natural Acyclovir
Acyclovir
substrate is converted
dGTPis converted to its
to
(deoxyguanosinemonophosphate
its monophosphate (ACV‐MP)
triphosphate)
ated diseases. Acyclovir is converted to its monophosphate (ACV‐MP) by the viral thymi‐ (ACV‐MP) by
and the
by
it viral
the
can thymi‐
viral
be a thymi‐
substrate for
dine
the kinase
dine kinase
viral (TK),
DNA
dine which
(TK), which
polymerase
kinase is further
(TK), which andphosphorylated
is further isthenphosphorylated
further be incorporatedby cellular
phosphorylated by cellular
toby kinases
the kinases
30 -end
cellular to kinases
ACV‐triphos‐
to a
of ACV‐triphos‐
synthesized
to ACV‐triphos‐ DNA
phate (ACV‐TP)
phate (ACV‐TP) (Figure
(Figure1). ACV‐TP,
1). ACV‐TP, 1).the active
the activeform of
0 -5acyclovir,
theform ofform ofisacyclovir,
acyclovir,
0 exonuclease a competitive
iscannot
a competitive inhibitor
inhibitor
molecule. phateThe(ACV‐TP)
DNA (Figure
polymerase-associated ACV‐TP, 3active is aexcise
competitive the 30 -terminal
inhibitor
withwith
respect to
respect
with the
to natural
the
respect natural
to substrate
the substrate
natural dGTP dGTP(deoxyguanosine
substrate (deoxyguanosine
dGTP triphosphate)
(deoxyguanosine triphosphate) and
triphosphate) it
and can be
it can
and abe 0
it acan be a
ACV-TP residues, resulting in prevention of chain elongation as ACV lacks the 3 hydroxyl
substrate
substratefor the
for viral
the
substrate for DNA
viral
for DNA DNA
the viralpolymerase
polymerase and
DNA polymerase then
and be
then incorporated
be
and has incorporated
thenlimited to
be incorporated the
to 3′‐end
the 3′‐endof a syn‐
of a syn‐
to the 3′‐end (15–30%) of a syn‐
groupDNA
thesized required molecule. The elongation.
DNA Acyclovir
polymerase‐associated 3′‐5′exonuclease oral bioavailability
cannot excise
thesized DNA
thesized molecule.
DNA The
molecule. DNA The polymerase‐associated
DNA polymerase‐associated
◦ 3′‐5′exonuclease
3′‐5′exonuclease cannot excise excise
cannot
theand
the restricted
3′‐terminal
3′‐terminal solubility
ACV‐TPACV‐TP
the 3′‐terminal residues, in water
residues,
ACV‐TP resulting (~0.2%,
resulting
residues, in 25
inresulting
prevention C), of
prevention requiring
chain
in preventionof chain relatively
elongation
ofelongation as ACV
chain elongation
large
as ACV doses
lacksaslacks
and fre-
ACV lacks
quent
the the administration
3′hydroxyl group to
required maintain plasma levels of acyclovir high enough to achieve viral
3′hydroxyl
the 3′hydroxylgroup groupfor
required DNA
for DNA
required elongation.
forelongation. Acyclovir
DNA elongation. Acyclovir has limited
has
Acyclovir limited orallimited
has bioavaila‐
oral bioavaila‐
oral bioavaila‐
inhibition.
bility (15–30%) The valine ester of acyclovir, valacyclovir (VACV, Valtrex, Zelitrex) large large2)
(Table
bility bilityand
(15–30%) restricted
and
(15–30%) andsolubility
restricted solubility
restricted in water
in water
solubility (~0.2%,
in(~0.2%,
water 25 °C),
25 °C),
(~0.2%, requiring °C),relatively
requiring
25 relatively
requiring large
relatively
is
doses a
dosessafe
andand and
frequent
doses
efficacious
andadministration
frequent prodrug
administration
frequent administration
(54%
to maintain
to maintainoral
toplasma
bioavailability).
plasma
maintain levels of acyclovir
levels
plasma of
levels
It is rapidly
ofhigh
acyclovir enough
high
acyclovir
metabolized
enough
highto enoughto to
to
achieve
yield
achieveviral
acyclovirinhibition.
and
viral the
viral inhibition.
achieve The valine
essential
The valine
inhibition. ester
Theamino of
ester acyclovir,
valineof acid
acyclovir,
ester Lof valacyclovir
-valine (VACV,
[26] valacyclovir
valacyclovir
acyclovir, due to Valtrex,
a carrier-mediated
(VACV, Zeli‐
Valtrex,Valtrex,
(VACV, Zeli‐ intesti-
Zeli‐
trex)
nal (Table
trex) (Table2) is(Table
absorption,
trex) 2)a isvia
safe
a 2) and
safe
the aefficacious
and
is humansafe efficacious
and prodrug
intestinal prodrug
efficacious (54%
peptide (54%
prodrug oral bioavailability).
oral
transporter
(54% bioavailability).
oral hPEPT1, It isIt
bioavailability). rapidly
is rapidly
followed It isby rapid
rapidly
metabolized
metabolized
conversion to toyield
metabolized acyclovir
toacyclovir
yield yield byand
toacyclovir thehydrolysis
and
ester
acyclovir essential
the and theamino
essential inamino
the
essential acid L‐valine
acid
small
amino ‐valine[26]
Lintestine.
acid due
[26]
L‐valine
to[26]
due
Several ato carrier‐
adue
carrier‐
clinical studies
to a carrier‐
mediated
mediated
demonstratedintestinal
intestinal
mediated absorption,
that absorption,
valacyclovir
intestinal via the
via
absorption, human
the
has aviahuman intestinal
safety intestinal peptide
profileintestinal
the human peptide
comparable transporter
transporter
peptide hPEPT1,
to transporterhPEPT1,
that of acyclovir fol‐ fol‐ infol‐
hPEPT1, HZ
lowedlowedby rapid
by rapidconversion
byconversion to acyclovir
to acyclovir by ester hydrolysis
byoption
esterbyhydrolysis in the small
in the inintestine.
small intestine. SeveralSeveralSeveral
patients. Valacyclovir
lowed became
rapid conversion a tobetter
acyclovir in
ester thehydrolysis
treatment of
theVZV smallinfections
intestine. since it
clinical studies
clinical studies demonstrated
demonstrated thatthatvalacyclovir
valacyclovir has a safety profile comparable to that of to
requires clinical
a less studies
frequent demonstrated
dosing regimen thanhas
that valacyclovir a safety
acyclovir, has a profile
safety
contributingcomparable
profile comparableto that
to increased of that of
patient
acyclovir
acyclovir in HZin
acyclovir patients.
HZ patients. Valacyclovir
Valacyclovir became became a better
a betteroptionoption
in HZ patients. Valacyclovir became a better option in the treatment of VZV in the
in treatment
the treatment of VZV
of VZV
adherence to therapy.
infections since it requires a less frequent dosing regimen than acyclovir, contributing to
infections since itsince
infections requires a less frequent
it requires dosing dosing
a less frequent regimen than acyclovir,
regimen contributing
than acyclovir, to
contributing to
increased patient
increasedincreasedadherence
patient adherence
patient to therapy.
to therapy.
adherence to therapy.
Table 2. Currently licensed anti-herpesvirus agents used to treat VZV infections. Anti-VZV drugs approved in United
States,
Table Europe
2.
Table and/or
Currently
2.Table
Currently Japan
licensed for treatmentagents
anti‐herpesvirus
licensed of VZV-associated
anti‐herpesvirus usedused
agents to treat diseases
VZV
to used
treat and drugs
infections.
VZV useddrugs
Anti‐VZV
infections. Anti‐VZV off drugs
label to treat
approved inacyclovir-resistant
United
2. Currently licensed anti‐herpesvirus agents to treat VZV infections. Anti‐VZVapproved in United
drugs approved in United
States, Europe
infections.
States, and/or
Europe Japan
and/or for treatment
Japan of VZV‐associated diseases and anddrugs usedused
off label to treat acyclovir‐resistant
States, Europe and/orfor treatment
Japan of VZV‐associated
for treatment diseases
of VZV‐associated drugs
diseases and drugsoffused
label to label
off treat acyclovir‐resistant
to treat acyclovir‐resistant
infections.
infections.
infections.
Mode of
Drug Prodrug Mode Modeof Action/Ap‐
of Action/Ap‐ Natural Analogue
Drug
Drug Drug Prodrug
Prodrug Mode of Action/Ap‐Natural
Action/Approval/Indication Analogue
Natural Analogue
Prodrug proval/Indication
proval/Indication Natural Analogue
I.I.Nucleoside analogues proval/Indication
I.Nucleoside
I. analogues
Nucleoside analogues
Nucleoside analogues
Acyclovir (ACV),
Acyclovir Zovirax
(ACV), Valaciclovir
ZoviraxZovirax
Acyclovir (ACV), (VACV),
Valaciclovir (VACV),
Valaciclovir Val‐Val‐ DNA
(VACV),  DNA
Val‐
• Polymerase
DNA Polymerase
Polymerase inhibi‐
DNA Polymerase inhibi‐2′‐Deoxyguanosine
2′‐Deoxyguanosine
inhibi‐ (natural
2′‐Deoxyguanosine(natural(natural
9‐(2‐hydroxyethoxyme‐
9‐(2‐hydroxyethoxyme‐ trex, Zelitrex
trex, Zelitrex tor—chain
tor—chain inhibitor—chain
terminator
terminator at the
at nucleoside)
the nucleoside)
9‐(2‐hydroxyethoxyme‐ trex, Zelitrex tor—chain terminator at the nucleoside)
thyl)guanine
thyl)guanine L‐valine ester
L‐valine of acyclovir
ester ofester
acyclovir incorporation terminator
incorporation site site at site
the
thyl)guanine L‐valine of acyclovir incorporation
incorporation site
O O
O
 FDA
 FDAapproved
approved
FDA approved HN HN
N N
• FDA approved HN
N
 Treatment
 Treatment andand suppres‐
suppres‐
• Treatment
Treatment and suppres‐ H N H NN NN H NN N N
and 2 2
2
sionsion
of VZV infections
of sion
VZV VZV (1st
ofinfections
suppression of (1st
infections
VZV (1st HO HO O O HO O
lineline
treatment
treatment for
infections
line VZV‐asso‐
for
treatmentVZV‐asso‐
(1stfor
lineVZV‐asso‐
ciated diseases)
ciated diseases)
treatment
ciated for
diseases) OH OH
OH
VZV-associated diseases)
Molecules 2021, 26, 1132 6 of 34
Table 2. Cont.
Molecules 2021,
Molecules
Molecules 26, 1132
2021,
2021, 26, 1132
26, 1132 66 of
of 35
635of 35
Molecules 2021, 26, 11322021, 26, 1132
Molecules
Mode of 6 of 35
Drug
Molecules 2021, 26, 1132 Prodrug Natural Analogue 66 of
of 35
35
Molecules 2021, 26, 1132 Action/Approval/Indication 6 of 35
Molecules 2021, 26, 1132 6 of 35
Penciclovir
Penciclovir (PCV),
Penciclovir
(PCV), Denavir,
(PCV),
Denavir, Famciclovir
Famciclovir (FAM), Famvir
(FAM),
(FAM), Famvir
Famvir  DNA
 DNA
DNA Polymerase
Polymerase
• Polymerase inhibi‐ 2′‐Deoxyguanosine
inhibi‐2′‐Deoxyguanosine
inhibi‐
DNA Polymerase 2′‐Deoxyguanosine (natural
(natural
(natural
Vectavir
VectavirPenciclovir
Penciclovir
Vectavir (PCV), Denavir,
Penciclovir (PCV), Diacetyl
Diacetyl
Denavir, ester
Diacetyl
Famciclovir
ester of 9‐(4‐hy‐
ester
of 9‐(4‐hy‐
(FAM),of 9‐(4‐hy‐
Famciclovir Famvir
(FAM), 
tor—chain
tor—chain
DNA
tor—chain
Famvir terminator
inhibitor—chain
terminator
Polymerase
terminator
 DNADNA after
inhibi‐
after
Polymerase nucleoside)
afternucleoside)
nucleoside)
inhibi‐ (natural
2′‐Deoxyguanosine (natural
Penciclovir (PCV),(PCV),
9‐(4‐hydroxy‐3‐hydroxyme‐
Vectavir
Denavir,
Famciclovir (FAM),
droxy‐3‐hydroxymethyl‐
Diacetyl ester of
(FAM),
9‐(4‐hy‐
droxy‐3‐hydroxymethyl‐ Famvir Famvir
 DNA
incorporation
incorporation
tor—chain
incorporation andand
terminator
and
Polymerase
Polymerase
elonga‐ inhibi‐
elonga‐
after
elonga‐
inhibi‐
nucleoside)
2′‐Deoxyguanosine (natural
(natural
Penciclovir Vectavir
Vectavir
(PCV), Denavir, Famciclovir Diacetyl
Diacetyl
(FAM), ester
ester of 9‐(4‐hy‐
 DNA
of 9‐(4‐hy‐
Famvir tor—chain
tor—chain
Polymerase terminator
terminator
inhibi‐ after
after nucleoside)
O
O
nucleoside)
O
(natural
Vectavir
thyl‐but‐1‐yl)guanine
thyl‐but‐1‐yl)guanine but‐ Diacetyl
but‐but‐ ester of
1‐yl)‐6‐deoxyguanine9‐(4‐hy‐
1‐yl)‐6‐deoxyguanine
1‐yl)‐6‐deoxyguanine tion tor—chain
tiontion
of several
of several
of several
incorporation andterminator
incorporation
bases
basesbases
elonga‐ after
and nucleoside) N N
Vectavir 9‐(4‐hydroxy‐3‐hydroxyme‐
Diacetyl droxy‐3‐hydroxymethyl‐
ester of 9‐(4‐hy‐ tor—chain incorporation
incorporation
terminator and elonga‐
and
after elonga‐
nucleoside)
HN OHN N
HN
O
O
O
thyl‐but‐1‐yl)guanine but‐ droxy‐3‐hydroxymethyl‐
1‐yl)‐6‐deoxyguanine tion incorporation
 FDA
FDA FDA
of elongation
approved
approved
several
approved basesandof elonga‐
several O
9‐(4‐hydroxy‐3‐hydroxyme‐ but‐
but‐ 1‐yl)‐6‐deoxyguanine
1‐yl)‐6‐deoxyguanine
droxy‐3‐hydroxymethyl‐ incorporation tion
tion of
of
and several
several
elonga‐ bases
bases H N HN
HN HN NN N
N
N N
HN
N
N
N 2
thyl‐but‐1‐yl)guanine but‐ 1‐yl)‐6‐deoxyguanine  tion
 Treatment
Treatmentof bases
several
of HZ bases O HN
HNN
2 2
FDA
FDA Treatment
approvedof
FDAHZof HZ
approved HN
N
thyl‐but‐1‐yl)guanine but‐ 1‐yl)‐6‐deoxyguanine tion of  •FDA
several FDA approved
bases
approved
approved
HO
H N HO NO
HO
HN O
N
O H HN
H N
N N NNN N
N
N 2
2
 Treatment  of HZ ofof
Treatment of HZ HN N
22
 FDA
2
• Treatment
Treatment
 Treatment
approved of HZ HZ
HZ HO
HN N
O HO
N HO
HO O
OO 2
HO
 Treatment of HZ HO
OH OH O
OH
O
OH OH
OH
OH
OH
OH
Brivudine,
Brivudine,
Brivudine, Zostex, Zonavir,
Zostex,
Zostex, Zonavir,
Zonavir, Orally
Orally
Orally
Orally bioavailable
bioavailable
bioavailable
bioavailable • Incorporation
•• Incorporation
Incorporation
• Incorporation intointo
into viral
viral into2′‐deoxythymidine
viral viral
2′‐deoxythymidine
2′‐deoxythymidine (natural
(natural
(natural
Zerpex
ZerpexBrivudine, DNA DNAwith DNA with
replication‐in‐ nucleoside)
Brivudine,
Zerpex Zostex, Zonavir, Orally bioavailable
Zostex, Zonavir, Orally bioavailableDNA withwith
• Incorporation replication‐in‐
into viral into
•replication‐in‐
Incorporation nucleoside)
nucleoside)
viral (natural (natural
Brivudine, Zostex, Zonavir, Orally bioavailable
(E)‐5‐(2‐bromovynil)‐2′‐de‐ • with
competent replication-incompetent
Incorporation
virus into viralnucleoside)
production 2′‐deoxythymidine
O (natural
(E)‐5‐(2‐bromovynil)‐2′‐de‐
Zerpex
Zerpex DNA competent
competent virus
DNA virus production
replication‐in‐
production
with replication‐in‐ O O
nucleoside)
Brivudine,
ZerpexZerpex
Zostex, Zonavir, Orally bioavailable • DNA DNA
Incorporation
virus
with with
into replication‐in‐
viral
production
replication‐in‐ nucleoside)
nucleoside) CH(natural
CH CH 3 3
oxyuridine
oxyuridine (BVDU), bromo‐
(BVDU), bromo‐
oxyuridine (BVDU), bromo‐
(E)‐5‐(2‐bromovynil)‐2′‐de‐ • Approved
• Approved
•competent
Approved in
virus some
in
in some
competent someEuro‐
production
Euro‐Euro‐
virus production
HN OHN
HN O
O
3
Zerpex (E)‐5‐(2‐bromovynil)‐2′‐de‐
(E)‐5‐(2‐bromovynil)‐2′‐de‐ • competent
DNAcompetent
with virus virus
Approved
replication‐in‐ in someproduction
productionnucleoside)O N CHO O
CH
vynildeoxyuridine
vynildeoxyuridine
oxyuridine (BVDU),
vynildeoxyuridine
oxyuridine bromo‐
(BVDU), bromo‐ pean
•
pean countries
pean countries
Approved
countries
• in some
Approved Euro‐
in some Euro‐ O HN O
N N HN
CH
CH
3
3
33
oxyuridine (BVDU),
(E)‐5‐(2‐bromovynil)‐2′‐de‐ bromo‐ competent European
•virus
Approved countries
in some
production Euro‐ O HN
CH
HN 3
oxyuridine
vynildeoxyuridine (BVDU), bromo‐ • • Approved
Treatment
•pean• Treatment
countries
Treatment of HZ
of HZ in some
of HZof HZ Euro‐ HO HO
HO
O OO NO
HN
oxyuridine vynildeoxyuridine
vynildeoxyuridine
(BVDU), bromo‐ • pean
• Approved pean countries
Treatment
countries
in some Euro‐ HN
CH
O
O
O N
N
N
3
vynildeoxyuridine pean countries

• Treatment of HZ
HO
O
O HON
HO
HO
• Treatment
• Treatment of HZ O
of HZof HZ
HO N O
O
vynildeoxyuridine pean•countries
Treatment O
OH OH
OH O
HO
• Treatment of HZ OH
O
OH OH
OH
OH
OH
II.
II.Nucleotide
II. Nucleotide
II.Nucleotide
Nucleotideanalogue analogue
analogue analogue
HPMPC,
II. HPMPC,
HPMPC, Cidofovir,
Nucleotide Cidofovir,
Cidofovir,
II. Vis‐Vis‐ analogue
analogue
Vis‐
Nucleotide Brincidofovir
Brincidofovir
Brincidofovir (BCV),
(BCV), (BCV), •• DNA
DNA
• DNA Polymerase
Polymerase
• Polymerase
DNA Polymerase inhibi‐
inhibi‐ 2′‐deoxycytidine
2′‐deoxycytidine
inhibi‐2′‐deoxycytidine 5′‐mono‐
5′‐mono‐
5′‐mono‐
®,II.
II. Nucleotide
Nucleotide analogue analogue
tide
HPMPC,
tide tide
® (S)‐1‐(3‐hydroxy‐2‐
®, (S)‐1‐(3‐hydroxy‐2‐
Cidofovir,
, (S)‐1‐(3‐hydroxy‐2‐
HPMPC, Vis‐
Cidofovir, CMX001,
CMX001,
Brincidofovir
CMX001,
Vis‐ hexadecyloxypro‐
hexadecyloxypro‐
(BCV),
hexadecyloxypro‐
Brincidofovir (BCV), tor—chain
• tor—chain
DNA
tor—chain terminator
terminator
Polymerase
•terminator
inhibitor—chain
DNA after
inhibi‐
after
Polymerase phosphate
phosphate
afterphosphate
inhibi‐ (natural
(natural
(natural nucleo‐
5′‐mono‐ nucleo‐
nucleo‐
2′‐deoxycytidine 5′‐mono‐
II. ®HPMPC, HPMPC,
Nucleotide Cidofovir,
analogue
Cidofovir, Vis‐ pyl‐cidofovir Brincidofovir
Vis‐Brincidofovir (BCV),(BCV), • DNA • DNAPolymerasePolymerase inhibi‐ inhibi‐ 2′‐deoxycytidine
2′‐deoxycytidine 5′‐mono‐ 5′‐mono‐
phosphonylmethoxypro‐
tide phosphonylmethoxypro‐
, (S)‐1‐(3‐hydroxy‐2‐
tide®,, (S)‐1‐(3‐hydroxy‐2‐
®® (S)‐1‐(3‐hydroxy‐2‐ pyl‐cidofovir
pyl‐cidofovir
CMX001, (HDP‐CDV)
(HDP‐CDV)
hexadecyloxypro‐
(HDP‐CDV)
CMX001, hexadecyloxypro‐ incorporation
incorporation
tor—chain
incorporation and
terminator
and
tor—chain elonga‐
and
elonga‐ elonga‐
after
terminator tide)
tide)
phosphate
tide) (natural
phosphate
after phosphate nucleo‐
(natural nucleo‐
nucleo‐
HPMPC,
pyl)cytosine
pyl)cytosine, tide
tide®Cidofovir,
(S)‐1‐(3‐hydroxy‐2‐
pyl)cytosine (HPMPC)
(HPMPC) (HPMPC)
Vis‐ Brincidofovir
CMX001,
pyl‐cidofovir
CMX001,
(BCV),
(HDP‐CDV)
hexadecyloxypro‐
hexadecyloxypro‐ • DNA
tiontion of several
incorporation
tion of
tor—chain
Polymerase
tor—chain
several incorporation
of several bases
and
bases bases
terminator
inhibi‐
terminator
elonga‐ and
after
aftertide)phosphate
5′‐mono‐
(natural (natural
NH2 NH2
nucleo‐
, (S)‐1‐(3‐hydroxy‐2‐
tide phosphonylmethoxypro‐ NH
CMX001, pyl‐cidofovir
pyl‐cidofovir
2 hexadecyloxypro‐
(HDP‐CDV)
(HDP‐CDV) tor—chain incorporation
incorporation
terminator and
and elonga‐
elonga‐ tide)
tide) NH 2
andafter phosphate
tide) (natural nucleo‐
® NH 2 NH
pyl)cytosine NH22 NH2
(HPMPC)
NH
pyl‐cidofovir
2 (HDP‐CDV) tion incorporation
of several elongation
bases elonga‐
of several
phosphonylmethoxypro‐pyl)cytosine
pyl)cytosine (HPMPC)
(HPMPC) pyl‐cidofovir
N NH (HDP‐CDV) incorporation tionand
tion of several
of several
elonga‐ bases
bases tide) NN NHN2 NH2
NH
NH
pyl)cytosine (HPMPC) N N2 NH
NH
NH 2
• tion
Cidofovir:
• of
Cidofovir: bases
several
off label
off bases
labeluse— use— NH2
22
N
N NH N 2 NH
NH222
NH NH 2
22
• Cidofovir: off label use— O N ONN
pyl)cytosine (HPMPC) tion of•several bases off label O N N
ofCidofovir:
NH2 NH2 NN
O NONH N O
N treatment ACV and/or
O N 2 N O
N
N O treatment
• Cidofovir:
treatment of of ACV
off
ACV label
and/or and/or
use— N
O NONH
O N N
N 2
N
N
N N
O
O O P O(CH
P O(CH
P 2))33O(CH
O(CH O(CH
) 2))15
O(CH CH
15CH ) 315 CH 3 • ••use—treatment
Cidofovir:
Cidofovir:
Cidofovir:
off label
off label
off label
of
use— ACVuse—
use— HO HO
HO
O
O O O
N
N
O
O
O N
N
N O
N
N O O N
O N
2 2 3
O
2 2 3 PFA‐resistant
PFA‐resistant
treatment
PFA‐resistant of VZV
ACV
VZV
treatment VZV infec‐
and/or
infec‐
of infec‐
ACV and/or
and/orHO
P O
P OP O O OO N
N
OHN OH O
O OO O O HO HO O
HO HO
HO O
N
N
O
OO N
N
N O ON OH
P O(CH O ) O(CH ) CH • Cidofovir:
treatment and/or
treatment
offoflabel
ACV PFA-resistant
of
use—ACV
and/or HO O
HO O
O
PP POO OO 2O 3 P O(CH
2 15O(CH2)))3O(CH
3
tions
O(CH )15CH
2tions
PFA‐resistant
tions CH VZV infec‐VZV OO
HO N O
N HO OO PP
P O(CH2)3 O(CH2)2153CH
O(CH 2 3 O(CH 22))15
15 CH333 PFA‐resistant
VZV
ACVinfections
PFA‐resistant VZV infec‐HO P HO O HO
O P P OO
infec‐ infec‐HO OHO P OHOHO
HO HO
HO O O O N HO
HO OOH
O treatment
3 of and/or HO P O O
O
O
P OO OHO
HO
HON PO O OH
OH
OH
••
tions • PFA‐resistant
Brincidofovir:
Brincidofovir:
Brincidofovir: VZV
herpesvirus
herpesvirus
herpesvirus
HO
O
HO
HOHO
HOP HO
P
P O
OO HO O P O(CH
HO
OH
2)3 O(CH2)15 CH 3
PFA‐resistant • tions
Brincidofovir:
tions VZV infec‐ P O OH OH
HO
HO O HO
HO tions HO O
HO O HO HO OH development
• development
Brincidofovir:
development discontinued
discontinued
herpesvirus
discontinued
P
HO
O
HO HO HO
tions • ••herpesvirus
Brincidofovir:
Brincidofovir:
Brincidofovir: herpesvirus
herpesvirus
herpesvirus OH OH
OH
OH
III. III. Pyrophosphate
Pyrophosphate HO analogue
HO analogue development OH
HO
III. Pyrophosphate HO analogue development discontinued
development
discontinued
• Brincidofovir: herpesvirus
•development discontinued OH
Foscarnet,
III.Foscarnet, Foscavir •• Direct
Direct DNA discontinued
polymerase
Foscarnet, III.Foscavir
Pyrophosphate
HO Foscavir
Pyrophosphate analogue analogue DirectDNA
DNA polymerase
polymerase
Foscarnet,III. Pyrophosphate
O Foscavir
analogue inhibitor
• inhibitor
Direct
inhibitor without
DNA without
without incorpora‐
polymerase incorpora‐
incorpora‐
III. Pyrophosphate
O OO
Foscarnet,
O O
analogue
Foscavir • Direct DNA polymerase
III. +Foscarnet,
Pyrophosphate Foscavir analogue • Direct DNA polymerase
Na O
Na + -- +-
O
Na P P
O CP CC tion
tion tion
inhibitor • without
Direct incorpora‐
DNA polymerase
Foscarnet, - Foscavir O
O-- Na
O
++- O + O • Direct inhibitor
DNAwithout
polymerase without incorpora‐
-
Na+ O O O +OO
O+ - Na
Na
P- NaC Na
Na
+ O Na
+ -O OP
++ --O C
O
••
tion
Off•inhibitor
Off label
Off
label useuse
label
use ‐‐ treatment
inhibitor
tion
treatment incorpora‐
‐ treatment
without of of
of
+ -O Na
NaO PO- C + -
P C inhibitor tion without incorpora‐
O- Na+O Na O O--- Na+++
++ O Na
acyclovir‐resistant
• Off acyclovir‐resistant
label incorporation
acyclovir‐resistant use
Off‐ label
VZV
treatment
VZV VZV in‐of
in‐ in‐
Na+ O P C O- Na+ OONa
- - -- Na
Na+ + tion • Off • label use ‐
use ‐ treatment
treatment of
of
O -
Na + fections
fections
fections •
acyclovir‐resistant Off label VZV
use—treatment
in‐ VZV in‐
-
O Na+ • Offacyclovir‐resistant
label use ‐ treatment
of acyclovir-resistantVZV of in‐
IV.IV.
IV. Non‐nucleoside
Non‐nucleoside
Non‐nucleoside analogue
analogueanalogue fections fections fections
fectionsVZV infections VZV in‐
Amenamevir
IV. Amenamevir
Amenamevir Non‐nucleoside {N‐(2,6‐dime‐
IV. {N‐(2,6‐dime‐{N‐(2,6‐dime‐
Non‐nucleosideanalogue Orally
Orally
Orally bioavailable
bioavailable
bioavailable
analogue ••Helicase‐primase
Helicase‐primase
• Helicase‐primase inhibitor
inhibitor
inhibitor
IV. IV. Non‐nucleoside
Non‐nucleoside analogue analogue fections
thylphenyl)‐N‐[2‐[4‐(1,2,4‐
Amenamevir
thylphenyl)‐N‐[2‐[4‐(1,2,4‐{N‐(2,6‐dime‐
Amenamevir Orally
{N‐(2,6‐dime‐ bioavailable
Orally bioavailable •• Approved
• Approved
Helicase‐primase
Approved • only
only onlyin
in Japan
in Japan inhibitor
inhibitor
Japan
Helicase‐primase
IV. Non‐nucleoside
AmenamevirAmenamevir {N‐(2,6‐dime‐
analogue
{N‐(2,6‐dime‐ OrallyOrally bioavailablebioavailable • Helicase‐primase inhibitor
oxadiazol‐3‐yl)anilino]‐2‐ox‐
thylphenyl)‐N‐[2‐[4‐(1,2,4‐ ••
••Treatment
Treatment
Approved Helicase‐primase
Treatment of HZ
only
of HZ
•Approvedofin
Approved HZ Japan inhibitor
only in in Japan
Japan
Amenamevir thylphenyl)‐N‐[2‐[4‐(1,2,4‐
{N‐(2,6‐dime‐
thylphenyl)‐N‐[2‐[4‐(1,2,4‐ Orally bioavailable • Helicase‐primase
• Approved • only
inhibitor
only in Japan
oethyl]‐1,1‐dioxothiane‐4‐
oxadiazol‐3‐yl)anilino]‐2‐ox‐ • Treatment • of HZ
Treatment of HZ
oxadiazol‐3‐yl)anilino]‐2‐ox‐ • Approved • Treatment• Treatment
only of in HZJapan of HZ
carboxamide}
carboxamide}
carboxamide}
oethyl]‐1,1‐dioxothiane‐4‐ • Treatment of HZ
carboxamide} carboxamide}
carboxamide}
carboxamide}
carboxamide}
O N
O N O treatment of ACV and/or
O N HO O
O P O(CH2)3 O(CH2)15 CH 3
O
PFA‐resistant VZV infec‐ HO
P O
O
HO OH
P O tions
HO HO
• Brincidofovir: herpesvirus OH
HO
Molecules 2021, 26, 1132 development discontinued 7 of 34
III. Pyrophosphate analogue
Foscarnet, Foscavir • Direct DNA polymerase
O
O
inhibitor without incorpora‐
-
Na+ O P C tion 2. Cont.
Table
O- Na+
O- Na+ • Off label use ‐ treatment of
Mode of
Drug Prodrug acyclovir‐resistant VZV in‐ Natural Analogue
Action/Approval/Indication
fections
IV.
IV.Non-nucleoside
Non‐nucleoside analogue
analogue
Amenamevir {N‐(2,6‐dime‐ Orally bioavailable
Orally bioavailable • Helicase‐primase
• inhibitor
Helicase-primase
thylphenyl)‐N‐[2‐[4‐(1,2,4‐ • Approvedinhibitor
only in Japan
oxadiazol‐3‐yl)anilino]‐2‐ox‐ •
• Treatment Approved
of HZ only in Japan
oethyl]‐1,1‐dioxothiane‐4‐ • Treatment of HZ
carboxamide}
Penciclovir [PCV, 9-(4-hydroxy-3-hydroxymethyl-but-1-yl)guanine, Denavir® , Vectavir® ],

a 20 -deoxyguanosine analog, resembles acyclovir in chemical structure, mechanism of action
and spectrum of antiviral activity (Table 2 and Figure 1) [27,28]. PCV-TP inhibits viral DNA
polymerases through competition with 20 -deoxyguanosine triphosphate and incorporation
into the synthesized viral DNA. Unlike ACV-TP, PCV-TP has two hydroxyl groups on the
acyclic chain and thus PCV-TP is not an obligate chain terminator and can be incorporated
into the extended DNA chain. Penciclovir is very poorly absorbed when given orally and
thus, famciclovir (FAM), the diacetylester of 6-deoxypenciclovir, was developed as the oral
prodrug, which has an oral bioavailability of 77%. Famciclovir is rapidly and extensively
absorbed and efficiently converted to penciclovir in two steps: (1) removal of the two acetyl
groups (the first one by esterases in the intestinal wall and the second one on the liver),
and (2) oxidation at the six position catalyzed by aldehyde oxidase that accounts for the
conversion of 6-deoxypenciclovir to penciclovir. Famciclovir is well tolerated in patients
and is effective against HSV-1 and HSV-2 (for both therapy and long-term suppression of
recurrent infections) and against VZV (for treatment of HZ).
Brivudine (BVDU), (E)-5-(2-bromovinyl)-20 -deoxyuridine, bromovinyldeoxyuridine
Zostex® , Zonavir® , Zerpex® (Table 2) is licensed for the therapy of HZ in several countries
in Europe. This thymidine analogue is a highly selective antiviral agent active against
HSV-1 and VZV [29]. Several congeners of brivudine have been synthesized, including
BVaraU (sorivudine), the arabinofuranosyl counterpart of brivudine. The selective anti-
HSV-1 and anti-VZV activity of brivudine is dependent on a specific phosphorylation of the
compound by the HSV-1 and VZV TK to its monophosphate (BVDU-MP) and diphosphate
(BVDU-DP) (Figure 2). Following conversion to the triphosphate form (BVDU-TP) by a
nucleoside diphosphate (NDP) kinase, BVDU-TP competes with the natural substrate dTTP
(deoxythymidine triphosphate) for the viral DNA polymerase, inhibiting the incorporation
of dTTP into the viral DNA or, as an alternate substrate is incorporated leading to the
formation of a structurally and functionally disabled viral DNA [29]. Approximately 90%
is absorbed following oral administration of brivudine and about 70% of the oral dose
is rapidly transformed to bromovinyluracil (BVU) during the first passage through the
liver [30]. Brivudine is effective in the treatment of HZ, both the short-term (formation
of new lesions) and long-term (prevention of PHN) effects, and is as efficient and/or
convenient as the other anti-VZV drugs acyclovir, valacyclovir and famciclovir. A recent
retrospective study compared efficiencies of valacyclovir, famciclovir and brivudine in
terms of pain relief in HZ patients [31]. All three drugs were effective in treating pain
in acute HZ with no significant difference between mild and moderate HZ patients. A
significant reduction in intensity of pain was observed in several cases on day 3 (brivudine
group), on day 7 (famciclovir group), and at 2–3 weeks (valacyclovir group). Significant
side effects were not observed in any of the groups. Based on the results of this study,
brivudine could be considered as the first choice to treat severe HZ cases considering that
is administered once daily and can control pain earlier.
Molecules 2021, 26, 1132 8 of 34
Molecules 2021, 26, 1132 8 of 35
Figure
Figure 1.1. Activation
Activation and and mechanism
mechanism of of action
action of of (A)
(A) acyclovir
acyclovir (ACV)
(ACV) and and penciclovir
penciclovir (PCV)
(PCV) andand (B)
(B) cidofovir
cidofovir (CDV)
(CDV) andand
foscarnet (PFA). Valacyclovir (VACV), the oral prodrug of ACV, has improved absorption compared to ACV because of
foscarnet (PFA). Valacyclovir (VACV), the oral prodrug of ACV, has improved absorption compared to ACV because of a
a stereo‐selective transporter in the human intestine by dipeptide transporters followed by rapid and efficient hydrolysis
stereo-selective transporter in the human intestine by dipeptide transporters followed by rapid and efficient hydrolysis to
to ACV by estereases found in the gut lumen, intestinal wall and liver. Famciclovir (FAM), the oral prodrug of PCV,
ACV byfirst
follows estereases found in
deacetylation at the
the 3gut
andlumen, intestinal
4 positions of thewall and side
acyclic liver.chain
Famciclovir
and then(FAM),
oxidationthe at
oral
theprodrug
6 position of of
PCV,thefollows
purine
first deacetylation at the 3 and 4 positions of the acyclic side chain and then oxidation
ring yielding the active metabolite, PCV. The conversion to the monophosphate (MP) forms of ACV and PCV is carried at the 6 position of the purine ring
yielding
out by thethe active
viral metabolite,
thymidine kinase PCV.
(TK). The
Theconversion
cellular enzyme to the guanosine
monophosphate (MP) forms
monophosphate of ACV
kinase and PCV kinase
or guanylate is carried
(GMP)out
by the viral
performs thymidine
further kinase (TK).
phosphorylation to The cellular enzyme
the diphosphate (DP)guanosine monophosphate
forms. Following conversion kinase or guanylate
to their triphosphate kinase
(TP)(GMP)
forms
by the cellular
performs further nucleoside 5′‐diphosphate
phosphorylation (NDP) kinase,
to the diphosphate (DP) the
forms.active metabolites
Following inhibittoviral
conversion theirDNA polymerases
triphosphate because
(TP) forms by
they act as competitive inhibitors
0 of the natural substrate (i.e., deoxyguanosine triphosphate,
the cellular nucleoside 5 -diphosphate (NDP) kinase, the active metabolites inhibit viral DNA polymerases because they act dGTP) and/or as alternative
substrates when
as competitive incorporated
inhibitors of theinto the growing
natural substrateDNA chain. Incorporation
(i.e., deoxyguanosine of ACV‐TP
triphosphate, into the
dGTP) growing
and/or DNA chain
as alternative results
substrates
in chain termination due to the lack of an OH at the 5′ position. PCV‐TP is not an obligate chain terminator due to the
when incorporated into the growing DNA chain. Incorporation of ACV-TP into the growing DNA chain results in chain
presence of an OH at the 5′ position and its 0incorporation results in slowdown of DNA chain elongation. The acyclic
termination due to the lack of an OH at the 5 position. PCV-TP is not an obligate chain terminator due to the presence
nucleotide analogue cidofovir (CDV) does not require activation by a virus‐encoded enzyme for activation as the molecule
0 position and its incorporation results in slowdown of DNA chain elongation. The acyclic nucleotide
of an OH
already at thea 5phosphonate
carries bond. In contrast to the O‐P linkage (phosphate), the CH2‐P‐bond (phosphonate) is resistant
analogue
to cidofovir (CDV)
phosphodiesterase and does not require
phosphatase activation
hydrolysis. by a virus-encoded
Therefore, enzyme phosphonates
acyclic nucleoside for activation as the molecule
(ANPs), such asalready
CDV,
carriesmimic
which a phosphonate bond.monophosphates,
the nucleoside In contrast to thecan O-P linkage
bypass the(phosphate), the CH2-P-bond
initial enzymatic phosphorylation (phosphonate) is resistant
by viral kinases. to
Similar
phosphodiesterase
to and phosphatase
a nucleoside monophosphate, hydrolysis.
a nucleoside Therefore, acyclic
phosphonate is furthernucleoside phosphonates
phosphorylated (ANPs),
by cellular such askinases.
nucleotide CDV, which The
conversion of CDV to its
mimic the nucleoside active metabolite,
monophosphates, cani.e.,bypass
CDV‐diphosphate (CDVpp)phosphorylation
the initial enzymatic is performed by cellular
by viralkinases
kinases.[UMP/CMP
Similar to
kinase 1 (UMP/CMPK‐1) and 5′‐diphosphate (NDP) kinase]. CDV‐DP, recognized
a nucleoside monophosphate, a nucleoside phosphonate is further phosphorylated by cellular nucleotide kinases. by the viral DNA polymerase, will then
The
block DNA synthesis by acting as competitive inhibitor with respect of the natural substrate
conversion of CDV to its active metabolite, i.e., CDV-diphosphate (CDVpp) is performed by cellular kinases [UMP/CMP dCTP or as alternative sub‐
strate leading to incorporation into the growing DNA. Chain termination occurs when two consecutive CDVpp’s are in‐
kinase 1 (UMP/CMPK-1) and 50 -diphosphate (NDP) kinase]. CDV-DP, recognized by the viral DNA polymerase, will then
corporated. CDVp‐choline is regarded as an intracellular reservoir of CDVp and CDVpp. Foscarnet (PFA, phosphonofor‐
block DNA synthesis by acting as competitive inhibitor with respect of the natural substrate dCTP or as alternative substrate
mic acid) does not require any activation by viral or cellular kinases and directly interacts with the viral DNA polymerase.
leading
PFA to incorporation
binds into the growing
to the pyrophosphate exchange DNA.
site of Chain termination
the viral occurs whenblocking
DNA polymerase, two consecutive
the releaseCDVpp’s are incorporated.
of pyrophosphate from
CDVp-choline
the is regarded
terminal nucleoside as an intracellular
triphosphate and thus,reservoir
impeding of CDVp and CDVpp.
the formation Foscarnet
of the (PFA, phosphonoformic
3′‐5′‐phosphodiester acid) does
linkage essential for
not require
viral any activation by viral or cellular kinases and directly interacts with the viral DNA polymerase. PFA binds to
DNA elongation.
the pyrophosphate exchange site of the viral DNA polymerase, blocking the release of pyrophosphate from the terminal
nucleoside triphosphate and thus, impeding the formation of the 30 -50 -phosphodiester linkage essential for viral DNA
elongation.
Molecules 2021, 26, 1132 9 of 34
Molecules 2021, 26, 1132 9 of 35
Figure 2. Activation,
Figure 2. Activation, mechanism
mechanism of of action
action and
and catabolism
catabolism of
of brivudine
brivudine (BVDU).
(BVDU). TheThe VZV
VZV thymidine
thymidine kinase
kinase (TK)
(TK) as
as well
well
as
as HSV-1 TK, display both thymidine kinase and thymidylate (dTMP) kinase activities, responsible for the activation of
HSV‐1 TK, display both thymidine kinase and thymidylate (dTMP) kinase activities, responsible for the activation of
BVDU to the monophosphate (BVDU‐MP) and diphosphate (BVDU‐DP) forms, respectively. The conversion of BVDU‐
BVDU to the monophosphate (BVDU-MP) and diphosphate (BVDU-DP) forms, respectively. The conversion of BVDU-
DP to the active triphosphate metabolite (BVDU‐TP) is carried out by the cellular nucleoside 5′‐diphosphate (NDP) kinase.
DP to the active triphosphate metabolite (BVDU-TP) is carried out by the cellular nucleoside 50 -diphosphate (NDP)
BVDU‐TP is recognized by DNA polymerases as an alternative substrate and is incorporated into the DNA molecule via
kinase. BVDU-TP
internucleotide is recognized
linkages. Pyrimidineby nucleoside
DNA polymerases
analogues,as such
an alternative
as BVDU and substrate andcan
BVaraU, is incorporated
be degraded by intopyrimidine
the DNA
molecule enzymes
catabolic via internucleotide linkages.
(such as uridine Pyrimidine or
phosphorylase nucleoside
thymidineanalogues, such as(TPase)
phosphorylase BVDUleading
and BVaraU,
to their can bebase
free degraded
metabo‐by
pyrimidine
lites withoutcatabolic
antiviralenzymes
activity.(such
BVDUas uridine phosphorylase
cannot be administeredortogether
thymidine phosphorylase
with 5‐flurouracil(TPase) leading capecitabine
or its prodrug to their free base
be‐
metabolites
cause without
BVU (the antiviral
product formedactivity. BVDUBVDU
following cannotdegradation
be administered
by thetogether with phsophorylase),
thymidine 5-flurouracil or its is prodrug
a potentcapecitabine
inhibitor of
dihydropyrimidine dehydrogenase.
because BVU (the product This enzyme
formed following BVDU is degradation
needed for theby first step in thephsophorylase),
the thymidine catabolic pathway is aofpotent
pyrimidines and
inhibitor of
for 5‐fluorouracil degradation
dihydropyrimidine and hence
dehydrogenase. Thisco‐administration
enzyme is neededof 5‐fluorouracil
for the first step and brivudine
in the catabolicleads to increased
pathway exposure
of pyrimidines to
and
5‐fluorouracil.
for 5-fluorouracil degradation and hence co-administration of 5-fluorouracil and brivudine leads to increased exposure to
5-fluorouracil.
One important limitation for the use of brivudine is the absolute contraindication of
the combination
One important of brivudine
limitation with 5‐fluorouracil
for the use of brivudine or itsis oral prodrug contraindication
the absolute capecitabine since of
BVU, the degradation product of brivudine, is a potent inhibitor
the combination of brivudine with 5-fluorouracil or its oral prodrug capecitabine since of dihydropyrimidine
dehydrogenase,
BVU, the degradation the enzyme
product responsible for the
of brivudine, is afirst step inhibitor
potent in the catabolic pathway of py‐
of dihydropyrimidine
rimidines
dehydrogenase,(Figurethe2). Dihydropyrimidine
enzyme responsibledehydrogenase
for the first step is needed
in the for 5‐fluorouracil
catabolic pathway deg‐
of
radation
pyrimidines and,(Figure
thereby2).concomitant administration
Dihydropyrimidine of 5‐fluorouracil
dehydrogenase is neededtogether with brivu‐
for 5-fluorouracil
dine results and,
degradation in increased exposure to administration
thereby concomitant 5‐fluorouracil of (since BVU hampers
5-fluorouracil 5‐fluorouracil
together with brivu-
dine results to
degradation in the
increased
inactiveexposure to 5-fluorouracil (since
5‐fluoro‐5,6‐dihydrouracil product, BVU hampers 5-fluorouracil
significantly increasing 5‐
degradationhalf‐life)
fluorouracil to the inactive 5-fluoro-5,6-dihydrouracil
[32]. Clinicians should thus be aware product, significantly increasing
of the life‐threatening and pos‐
5-fluorouracil
sible half-life)interaction
fatal drug‐drug [32]. Clinicians should thus
of brivudine and be aware of the life-threatening
capecitabine/5‐fluorouracil and
[33–35].
possible fatallike
Sorivudine, drug-drug
brivudine, interaction of brivudine
is metabolized to BVUand andcapecitabine/5-fluorouracil
therefore, its administration [33–35].
with
Sorivudine, like
5‐fluorouracil brivudine, is metabolized
is contraindicated. Sorivudine, to BVU
licensedandin therefore,
Japan inits administration
1993 with
for the treatment
5-fluorouracil
of HZ, was withdrawnis contraindicated.
following Sorivudine,
several deaths licensed
relatedintoJapan in 1993 for the treatment
the co‐administration with 5‐
of HZ, was [36,37].
fluorouracil withdrawn following several deaths related to the co-administration with
5-fluorouracil [36,37].
The helicase‐primase inhibitor (HPIs) amenamevir {ASP2151, N‐(2,6‐dime‐
The helicase-primase inhibitor (HPIs) amenamevir {ASP2151, N-(2,6-dimethylphenyl)-
thylphenyl)‐N‐[2‐[4‐(1,2,4‐oxadiazol‐3‐yl)anilino]‐2‐oxoethyl]‐1,1‐dioxothiane‐4‐carbox‐
N-[2-[4-(1,2,4-oxadiazol-3-yl)anilino]-2-oxoethyl]-1,1-dioxothiane-4-carboxamide}
amide} (Table 2) was approved for treatment of HZ in Japan in September 2017 while (Tablethe
2)
was approved
phase for this
I trial with treatment
drug wasof HZ in Japan
halted in September
in United States due 2017towhile
safetythe phase I trial
concerns. The with
her‐
this drughelicase–primase
pesvirus was halted in United States
complex due to safetythe
(encompassing concerns.
helicase,The theherpesvirus
primase andhelicase–
a cofac‐
primase complex (encompassing the helicase, the primase
tor protein with 1:1:1 stoichiometry) possesses multiple enzymatic activitiesand a cofactor protein including
with 1:1:1
Molecules 2021, 26, 1132 10 of 34
stoichiometry) possesses multiple enzymatic activities including DNA helicase, single-

stranded DNA (ssDNA)-dependent ATPase and primase, all essential for viral DNA
replication and viral growth. Agents targeting the helicase–primase complex represent
a breakthrough in the development of anti-herpesvirus agents. The helicase–primase
complex is well conserved among members of the herpesvirus family and genes encoding
the VZV helicase subunit (ORF55), primase subunit (ORF6) and cofactor subunit (ORF52)
share homology with, respectively, the HSV-1 UL5, UL52, and UL8 genes and with the
HCMV genes UL105, UL70 and UL102.
Amenamevir is an oxadiazole phenyl derivative with potent activity against both
VZV and HSV [38], while the two other classes of HPIs, i.e., the thiazole urea derivative
Pritelivir (AIC316, BAY 57-1293) and the 2-aminothiazolylphenyl type, BILS 179 BS, have
a limited antiviral spectrum inhibiting only HSV-1 and HSV-2. HPIs are virus-specific,
have low in vitro toxicity, inhibit both reference and clinical viral strains, and are orally
bioavailable and effective in different mouse models of HSV infection. They have a com-
pletely different mechanism of action (direct inhibition of the helicase-primase complex)
compared to the classical anti-herpesvirus agents (target the DNA polymerase) and do
not need activation by the viral TK. Thus, HPIs are active against viral mutants with a
defective TK (TK−). Furthermore, combination of HPI with nucleoside analogues showed
a synergistic effect in vitro, pointing at combination therapy as a potential approach for
treating severe conditions, such as encephalitis or infections in patients with immunosup-
pression [39,40]. To confirm that the anti-VZV activity of amenamevir was due to inhibition
of the VZV helicase-primase complex, an amenamevir VZV mutant was selected and
characterized [41]. Sequencing analysis of ORF55 (helicase gene) and ORF6 (primase gene)
of this mutant indicated three amino acid changes from the parent strain: N336K in the
helicase motif IV, one of the six well-conserved sequence motifs in ORF55, R446H in ORF55
and N939D in ORF6. Notably, this mutant showed a marked defect in viral replication.
Astellas Pharma originally developed amenamevir for treatment of genital herpes and
HZ. The efficacy of amenamevir 2× daily was comparable to acyclovir twice a day (BID)
for 3 days using the primary endpoint ‘time to lesion healing’ in a phase II dose-finding
study in patients with genital herpes (NCT00486200) [42]. Time to healing was shorten by
1–2 days in both treatment groups compared to the placebo group. The results of the clinical
trial (NCT00487682), sponsored by Astellas Pharma, to investigate the efficacy and safety
of three different doses of ASP2151 compared to valacyclovir in subjects with HZ and to
determine the recommended clinical dose, have not yet been reported. Following a phase
1, randomized, double blind, multiple dose, multicenter study (NCT00870441) to compare
the safety of amenamevir to valacyclovir and placebo in healthy male and female subject,
Astellas Pharma halted the clinical development of amenamevir due to treatment-emergent
serious adverse events. Maruho Co., Ltd. (Kyoto, Japan) resumed the development of
amenamevir and conducted a randomized, double-blind, valacyclovir-controlled phase
3 study to evaluate the efficacy and safety of amenamevir in Japanese HZ patients that
receive the drug within 72 h following the start of the rash. The study included 751 patients
who were randomly distributed to be treated with either amenamevir 400 mg or 200 mg
per os, 1× per day or valacyclovir 1000 mg 3× per day (3000 mg total daily dose) for
7 days (NCT01959841) [43]. The cessation proportion of development of new lesions at
day 4, i.e., day 4 cessation proportion, was considered the primary efficacy end-point and
these proportions were 81.1% (197/243), 69.6% (172/247) and 75.1% (184/245), respectively,
for amenamevir 400 and 200 mg and valacyclovir, with non-inferiority of amenamevir
400 mg to valacyclovir confirmed by a closed testing procedure. Secondary end-points
(days to cessation of new lesions formation, complete crusting, healing, pain resolution and
virus disappearance) were not significantly different among the three treatment groups.
Amenamevir (400 and 200 mg) and valacyclovir 3000 mg were well tolerated and the
proportions of patients experiencing drug-related adverse events were 10.0% (25/249),
10.7% (27/252) and 12.0% (30/249), respectively. This study showed that amenamevir
Molecules 2021, 26, 1132 11 of 34
400 mg is effective and well tolerated for treatment of HZ in immunocompetent Japanese

patients, leading to amenamevir approval for this indication in Japan.
Cidofovir, the first FDA-approved acyclic nucleoside phosphonate (ANP) for intra-
venous treatment of HCMV retinitis in AIDS patients in 1996, is mostly used off-label for
the intravenous or topical treatment of severe infections caused by various DNA viruses,
including various herpesviruses other than HCMV, polyoma-, adeno-, pox- (molluscum
contagiosum virus and orf virus) and human papillomaviruses (HPV). In the case of VZV,
the drug is used off label for therapy of acyclovir and/or foscarnet resistant infections. Cid-
ofovir has a phosphonate group bypassing the first phosphorylation step by viral kinases.
Cellular kinases convert the drug to the active diphosphate form (CDVpp), which acts as a
competitive inhibitor of the viral DNA polymerase, causing slow down elongation and
premature chain termination during viral DNA synthesis (Figure 1). CDVpp inhibits viral
DNA polymerases more potently than cellular DNA polymerases. The metabolites of the
ANPs show an unusually long intracellular half-life, accounting for a long-lasting antiviral
activity. The formation of CDVp-choline adduct serves as an intracellular reservoir for
the mono-(CDVp) and diphosphonate (CDVpp), explaining the long-lasting activity of
the drug. CDV has two important drawbacks that restrict its use in clinic. Due to its low
oral bioavailability (<5%), the drug needs to be administered intravenously, normally once
a week because of its long-lasting activity. CDV is also known for its dose dependent
nephrotoxicity, which can be reduced by pre-hydration with at least 1 L of 0.9% saline
solution intravenously before each CDV infusion and concomitant oral administration of
probenecid.
The pyrophosphate analogue foscarnet (PFA, Foscavir® ), a direct inhibitor of viral
DNA polymerases, is independent of activation by the viral TK (Figure 1 and Table 2).
Hence, PFA is the therapy of choice for acyclovir-resistant (ACV-R) VZV infections due to
mutations in the viral TK gene,
5. Medical Need for New Antiviral Agents to Manage VZV-Associated Diseases

5.1. Management of PHN and other Complications
Current antiviral drugs available for HZ treatment significantly decrease the incidence
of new lesion formation, accelerate healing, and shorten the duration of viral shedding
thereby reducing the incidence, severity and duration of pain, and limiting neuron dam-
age [44]. The effect on the resolution of pain is extremely important in the antiviral therapy
of HZ. Pain associated with HZ can be measured in three ways: (i) pain at presentation
(acute pain), quantified over the first 30 days; (ii) PHN (post-herpetic neuralgia), defined
as “pain that has not resolved after 30 days of disease onset" or as “pain that persists
after healing or pain 90 days after rash onset” and (iii) zoster-associated pain (ZAP), pain
recorded from the time of acute zoster until its complete resolution [44].
Acyclovir, valacyclovir and famciclovir are approved worldwide for the treatment of
HZ in both immunocompetent and immunocompromised patients, brivudine is available
in some European countries, and amenamevir is licensed only in Japan. Valacyclovir
proved superior to acyclovir according to ZAP analysis from different clinical studies [44].
Famciclovir and acyclovir were therapeutically equivalent in terms of healing rate and
pain resolution in immunocompetent patients aged >50 years. Brivudine proved similar
efficacy on pain and rash as well as a similar tolerability compared to famciclovir in a large
multicenter study that enrolled patients with acute HZ aged ≥50 years [44].
However, existing antiviral therapies are not completely effective in avoiding PHN,
most likely because antivirals should be started within 72 h of rash appearance. The delay
between onset of symptoms and start of treatment is likely the major cause of reduced
efficacy of antiviral therapy. Clinical trials of antiviral drugs for HZ have enrolled patients
within 72 h from rash onset; however, no well-controlled clinical trials comparing early-
onset therapy with later therapy (>72 h) have been performed. Therefore, antiviral agents
with a higher potency may achieve a more rapid decrease in viral replication consequently
reducing neural damage and both acute and chronic symptoms of HZ. In addition, currently
Molecules 2021, 26, 1132 12 of 34
available antivirals require 3–5 times daily dosing regimens that need to be modified for
patients with renal impairment. The medications used to treat the pain associated with
PHN are only palliative, are often insufficient in terms of relief for the patients and do
not provide a cure for HZ. Hence, drugs with superior anti-VZV activity, with the ability
to prevent PHN, able to provide better pain relief, and with a more simplified dosing
regimen are indeed needed. These drugs would also be very useful for the management of
disseminated VZV primary infections and complications of VZV reactivation, including
VZV vasculopathy, meningoradiculitis, cerebellitis, myelopathy, ocular disease, and zoster
sine herpete (ZSH, radicular pain in the absence of skin rash).
5.2. Managing Rare but Significant Side Effects Linked to the VZV Life Vaccine
The varicella vaccine in infants diminishes the consequences of chickenpox in terms of
both healthcare and economic burden, while the zoster vaccine protects immunocompetent
adults from HZ and reduces disease severity in those who develop HZ. Adverse events
were not seen in clinical trials performed with the VZV vaccines. However, rare but
important side effects are being increasingly described most likely due to the increased
administration of VZV life vaccines worldwide.
A few cases of disseminated varicella infections due to the VZV vaccine strain were
described in immunocompromised patients, requiring treatment with antiviral agents [45,46].
VZV vaccine can occasionally reactivate in healthy children and cause HZ [47,48] and
in adults [49]. A disseminated VZV infection with CNS involvement directly following
vaccine administration has been reported in a previously healthy elderly woman [50].
Herpes zoster and meningitis due to reactivation of the VZV vaccine virus has been
described in an immunocompetent child [51]. Also, a case of vaccine-associated HZ
ophtalmicus and encephalitis in an immunocompetent child requiring acyclovir therapy
has been described [52].
Clinicians should also be aware that very rarely, the varicella vaccine can be transmit-
ted and cause invasive disease as shown by a case report showing that the VZV vaccine
was transmitted within a family from a child with shingles resulting in varicella meningitis
in an immunocompetent adult [53].
Therefore, antiviral therapy will be needed for treatment of rare VZV diseases even
after widespread implementation of vaccination programs.
5.3. Emergence of Drug-Resistant Viruses

Treatment of VZV infections with acyclovir or valacyclovir in the immunocompe-
tent hosts is not associated with emergence of. In the immunocompromised hosts, VZV
infection tends to be severe and persistent, requiring prolonged therapy with antivirals
and ACV-R mutants have been isolated after long-term treatment with acyclovir [54–58].
Persistent VZV and VZV-related complications occur more frequently among hematolog-
ical patients and antiviral resistance was found in 27% of patients with persistent VZV,
including patients that progressed to severe retinal or cerebral infection [59]. Besides,
compartmentalization of ACV-R VZV has been reported with important implications for
sampling in molecular diagnostics [60]. Notably, ACV-R VZV keratitis was reported in an
immunocompetent patient [61], highlighting the need to determine the antiviral-resistance
patterns of corneal VZV isolates from chronic keratitis even in immunocompetent patients,
as the eye can be considered an immune privileged site.
Resistance to acyclovir in VZV appears because of mutations in either the TK or the
DNA polymerase genes. The most frequent mutants isolated both in cell culture and in the
clinic are TK mutants [62,63]. Mutations associated with resistance to nucleoside analogues
are distributed throughout the entire VZV TK gene, similarly to HSV-1 and HSV-2. How-
ever, conserved regions, such as the ATP- and the nucleoside-binding sites, and the amino
acid position 231 are considered as hot spots for drug-resistance mutations [56,57,64–66].
Several case reports documented the use of foscarnet as salvage therapy for ACV-R VZV
infections in immunocompromised patients [67–69]. However, mutations in the VZV DNA
Molecules 2021, 26, 1132 13 of 34
polymerase gene associated with PFA-R have also been described in immunocompromised
patients [70–72]. The amino acid changes in the VZV DNA polymerase linked to PFA-R
show generally cross-resistance to acyclovir. Remarkably, acyclovir and penciclovir were
shown to select in vitro for different types of drug-resistant VZV genotypes: TK mutants
under acyclovir pressure and DNA polymerase mutants under penciclovir selection [63,73].
This is different from HSV findings, where both drugs selected in vitro for TK mutants.
Penciclovir remains active against some HSV-1 and VZV TK and DNA polymerase mutants
that show ACV-R [74–76], indicating that the interactions between human α-herpesviruses
TK and penciclovir or acyclovir, and also between the viral DNA polymerases and PCV-
TP or ACV-TP are dissimilar, which may explains the differences between ACV-R and
PCV-R VZV strains. Additionally, the frequency of VZV mutants was significantly higher
following acyclovir pressure than penciclovir exposure [77]. As cidofovir (CDV, HPMPC)
(Table 2) is a nucleotide analogue that is converted to the active form CDVpp, by cellular
kinases, it is a therapeutic option for therapy of ACV-R, PCV-R and/or PFA-R resistant
VZV infections [21,78,79].
Emergence of ACV-R in the course of a chronic infection caused by the Oka vaccine
VZV strain was reported in an immunosuppressed child vaccinated prior a tumor diagnosis
requiring intensive antitumor therapy [80]. Clinical ACV-R in this patient was linked to a
TK mutation that responded to foscarnet therapy. ACV-R in the Oka vaccine strain was
also described in a child with neuroblastoma [69], suggesting that the Oka vaccine strain
can be linked to severe disease in the immunocompromised host following reactivation
from latency, being necessary prolonged acyclovir therapy with the subsequent risk of
emergence of drug-resistance. Hence, novel potent anti-herpesvirus agents with a target
other than the viral DNA polymerase would be very useful to manage drug-resistance to
the currently available antiviral agents.
6. Novel Anti-VZV Agents in Advanced Development

The gold standard for VZV therapy remains acyclovir and its prodrug valacyclovir.
Other nucleoside analogues such as penciclovir, its prodrug famciclovir and brivudine can
also be used. These antiviral agents rely on the viral TK for their first phosphorylation
and have as target the viral DNA polymerase. VZV mutants arising under pressure with
these nucleoside analogues bearing mutations in the viral TK can be treated with foscarnet,
a direct inhibitor of viral DNA polymerases. However, foscarnet can be associated with
significant renal toxicity and cannot be used for VZV DNA polymerase mutants emerging
under acyclovir as most of them show cross-resistance to foscarnet. As cidofovir is a nu-
cleotide analogue that bypass the activation by the viral TK and usually DNA polymerase
mutants that are resistant to acyclovir and/or foscarnet remain sensitive to cidofovir, this
drug can be used for VZV infections refractory to acyclovir, penciclovir and/or foscarnet.
Unfortunately, cidofovir can also cause renal toxicity. Amenamevir, an helicase-primase
inhibitor, has only been approved in Japan and its development was discontinued in
United States due to toxicity concerns. The drawbacks of the currently available treatments
for VZV-associated diseases highpoint the necessity for new, safe and highly effective
anti-VZV agents. Drugs able to inhibit virus growth by targeting different steps of the VZV
replicative cycle will be very useful for the management of drug-resistance infections in
the clinic as well as for limiting the probability of emergence of antiviral drug-resistance
and could also form the base for combination therapy.
Research should focus on the discovery and development of new anti-herpesvirus
compounds having more potent activity than the currently available VZV antivirals. Be-
sides, the search of new lead compounds able to block viral enzymes other than the viral
DNA polymerase should be favored. In the last decade, only a few anti-VZV drugs were
compared to valacyclovir in clinical trials to evaluate their efficacy in diminishing HZ
associated pain and severity.
Molecules 2021, 26, 1132 14 of 34
Molecules 2021, 26, 1132 14 of 35
6.1. Bicyclic Nucleoside Analogues (BCNAs)

6.1. In
Bicyclic
1999,Nucleoside
the potentAnalogues (BCNAs)
and selective anti-VZV activity of some unusual bicyclic nucleoside
In 1999,
analogues the potent
(BCNAs) wasand selective
reported by anti‐VZV
Mc Guigan activity of some unusual
and collaborators [81].bicyclic nucleo‐
For BCNAs with
side analogues (BCNAs) was reported by Mc Guigan and collaborators [81].
simple alkyl side-chain on the bicyclic base ring, the optimal carbon chain length for anti- For BCNAs
withactivity
VZV simple alkyl
rankedside‐chain
between on8the bicyclic
and basethe
10, with ring, the optimal carbonderivative
6-octyl-substituted chain length for
Cf-1368
anti‐VZV
being activity
the most ranked
active between 8compound
and selective and 10, with the series
of this 6‐octyl‐substituted
of BCNAs. derivative Cf‐
1368Although
being the most
BCNAs active
areand selective compound
structurally related to of this series
BVDU, theyofdiffer
BCNAs. in their spectrum
of antiviral activity as they exclusively inhibit VZV, in contrast to BVDU spectrum
Although BCNAs are structurally related to BVDU, they differ in their of
that possesses
antiviral activity as they exclusively inhibit VZV, in contrast to BVDU
potent anti- HSV-1 and anti-VZV activity. Among BCNAs with an aromatic ring system that possesses po‐
tent anti‐
(phenyl) in HSV‐1 and anti‐VZV
the side-chain, activity. Among
the n-pentylphenyl- andBCNAs with an aromatic ring
n-hexylphenyl-derivatives systemand
(Cf-1742
(phenyl) in the side‐chain, the n‐pentylphenyl‐ and n‐hexylphenyl‐derivatives (Cf‐1742
Cf-1743, respectively) (Figure 3) emerged as the most potent compounds with 50% effective
and Cf‐1743, respectively) (Figure 3) emerged as the most potent compounds with 50%
concentration (EC50 ) values as low as 0.0001–0.0005 µM against reference VZV strains
effective concentration (EC50) values as low as 0.0001–0.0005 μM against reference VZV
as well as clinical isolates in vitro [82,83]. A strong correlation between the length of the
strains as well as clinical isolates in vitro [82,83]. A strong correlation between the length
n-alkyl and n-alkylaryl moiety of the BCNAs and antiviral activity was observed [84]. Cf-
of the n‐alkyl and n‐alkylaryl moiety of the BCNAs and antiviral activity was observed
1743 was also able to reduce the replication and spread of VZV in organotypic epithelial raft
[84]. Cf‐1743 was also able to reduce the replication and spread of VZV in organotypic
cultures as measured by morphological changes induced by the virus and quantification
epithelial raft cultures as measured by morphological changes induced by the virus and
of the viral DNA load [85]. Similar to acyclovir and brivudine, the BCNAs were inactive
quantification of the viral DNA load [85]. Similar to acyclovir and brivudine, the BCNAs
against TK-deficient
were inactive against(TK −) strains, pointing
TK‐deficient to a crucial
(TK−) strains, roletoofa the
pointing VZV-encoded
crucial role of theTK in the
VZV‐
activation (phosphorylation) of the BCNAs. VZV mutant strains
encoded TK in the activation (phosphorylation) of the BCNAs. VZV mutant strains se‐selected in vitro under
pressure
lected inof BCNAs
vitro undershowed
pressuremutations
of BCNAsinshowed
the viral TK genein[63].
mutations the viral TK gene [63].
Figure
Figure 3. 3.Anti-VZV
Anti‐VZV drugs
drugs in
inadvanced
advanced development.
development.Chemical structures
Chemical of CF‐1743
structures and its prodrug
of CF-1743 and its valnivudine hydro‐
prodrug valnivudine
chloride (FV‐100) and of omaciclovir (H2G) and its prodrug valomaciclovir stearate.
hydrochloride (FV-100) and of omaciclovir (H2G) and its prodrug valomaciclovir stearate.
BCNAs also strikingly differ from brivudine in their mechanism of activation (Figure
BCNAs also strikingly differ from brivudine in their mechanism of activation
4) [86,87]. BCNAs are recognized by VZV TK as a substrate, but not by HSV‐1 TK, nor by
(Figure 4) [86,87]. BCNAs are recognized by VZV TK as a substrate, but not by HSV-1 TK,
cytosolic TK‐1 or mitochondrial TK‐2 in kinetic studies with purified enzymes [84]. VZV
nor by cytosolic TK-1 or mitochondrial TK-2 in kinetic studies with purified enzymes [84].
TK was demonstrated to phosphorylate the BCNAs not only to their corresponding 5′‐
VZV TK was demonstrated to phosphorylate the BCNAs not only to their corresponding
mono‐ but also to their 5′‐diphosphate derivatives due to the intrinsic dTMP kinase activ‐
50 -mono- but also to their 50 -diphosphate derivatives due to the intrinsic dTMP kinase ac-
ity of the VZV TK. Thus, BCNAs are selectively phosphorylated to their 5′ diphosphates
tivity of the VZV TK. Thus, BCNAs are selectively phosphorylated to their 50 diphosphates
by the two successive enzyme activities of VZV TK (thymidine kinase and dTMP kinase).
by the two successive enzyme activities of VZV TK (thymidine kinase and dTMP kinase).
However, no clear-cut correlation between the antiviral potency of the compounds and
Molecules 2021,
Molecules 26, 26,
2021, 11321132 1535of 34
15 of
However, no clear‐cut correlation between the antiviral potency of the compounds and
their affinity for VZV TK could be demonstrated, pointing to a different structure/activity
their affinity for VZV TK could be demonstrated, pointing to a different structure/activity
relationship of the eventual antiviral target of these compounds. In contrast to BVDU,
relationship of the eventual antiviral target of these compounds. In contrast to BVDU,
human NDP kinase was unable to convert BCNAs to their triphosphate derivatives (BCNA-
human NDP kinase was unable to convert BCNAs to their triphosphate derivatives
TP) [84], in agreement with studies reporting no traces of BCNA-TP in VZV infected cells.
(BCNA‐TP) [84], in agreement with studies reporting no traces of BCNA‐TP in VZV in‐
These data clearly indicate that the mechanism of action of BCNAs differs from that of
fected cells. These data clearly indicate that the mechanism of action of BCNAs differs
BVDU and suggests that BCNAs exert their antiviral effects via their monophosphate or
from that of BVDU and suggests that BCNAs exert their antiviral effects via their mono‐
diphosphate derivatives, virtually excluding the DNA polymerase as the molecular target
phosphate or diphosphate derivatives, virtually excluding the DNA polymerase as the
ofmolecular
the BCNAs. Theofexact
target molecular
the BCNAs. Thetarget
exactof the BCNAs
molecular could
target notBCNAs
of the be identified
could yet
notand
be is
currently under investigation.
identified yet and is currently under investigation.
Figure
Figure 4. Activation,
4. Activation, mechanismofofaction
mechanism actionand
andcatabolism
catabolism of
of bicyclic
bicyclic nucleoside
nucleosideanalogues
analogues(BCNAs).
(BCNAs). VZV
VZVTKTKconverts
converts
BCNA’s to the mono‐ and diphosphate forms although whether there is conversion to the triphosphate form and which
BCNA’s to the mono- and diphosphate forms although whether there is conversion to the triphosphate form and which is
is the active metabolite and mechanism of action remain unclear to date. Striking differences between BCNAs and BVDU
theexist
active metabolite
regarding and
their mechanism
catabolic of action
pathways. remain to
In contrast unclear
BVDU,tohuman
date. Striking differences
TPases do between
not recognize BCNAs
BCNA’s and BVDU
as substrates exist
and
regarding
the free bases of BCNAs do not inhibit human DPD (dihydropyrimidine dehydrogenases) and thereof, there is a normalfree
their catabolic pathways. In contrast to BVDU, human TPases do not recognize BCNA’s as substrates and the
bases of BCNAsofdo
metabolism not inhibit human DPD (dihydropyrimidine
Capecitabine/5‐fluorouracyl. Dashed grey arrowsdehydrogenases) and thereof, there is a normal metabolism
indicate lack of activation.
of Capecitabine/5-fluorouracyl. Dashed grey arrows indicate lack of activation.
BCNAs have also different catabolic pathways than BVDU and BVaraU (Figure 4),
BCNAs
providing have also
BCNAs withdifferent
significantcatabolic
advantages.pathways thannucleoside
Pyrimidine BVDU and BVaraU are
analogues (Figure
sus‐ 4),
providing
ceptible toBCNAs with catabolic
pyrimidine significant advantages.
enzymes (such Pyrimidine nucleoside analogues
as uridine phosphorylase are sus-
or thymidine
phosphorylase
ceptible and are catabolic
to pyrimidine hydrolyzed to their free
enzymes (such base metabolites
as uridine that lack antiviral
phosphorylase activ‐
or thymidine
ity. In contrast,and
phosphorylase BCNAs were not recognized
are hydrolyzed as substrates
to their free by human
base metabolites thymidine
that phosphor‐
lack antiviral activity.
Inylase and thereby
contrast, BCNAs they were
were notrecognized
not converted toastheir inactiveby
substrates freehuman
base derivatives
thymidine [88]. Fur‐
phospho-
thermore,
rylase and the free bases
thereby they of BCNAs
were not were not inhibitory
converted to their to humanfree
inactive dihydropyrimidine
base derivatives de‐[88].
hydrogenase,the
Furthermore, thefree
catabolic
bases enzyme
of BCNAs involved in the
were not degradation
inhibitory of pyrimidines
to human analogues. de-
dihydropyrimidine
hydrogenase, the catabolic enzyme involved in the degradation of pyrimidines analogues.
As mentioned above, the BVU free base is inhibitory to dihydropyrimidine dehydrogenase,
an enzyme necessary for the catabolic inactivation of the chemotherapeutic pyrimidine
analogue 5-fluorouracil.
Molecules 2021, 26, 1132 16 of 34
The safety of the oral prodrug of Cf-1743, i.e., FV-100 (valnivudine hydrochloride),
was evaluated in three randomized, double-blind, placebo-controlled clinical trials: (i) a
single-ascending-dose study in 32 healthy subjects aged 18 to 55 years (100-, 200-, 400-, and
800-mg doses); (ii) a multiple-ascending-dose study including 48 subjects (18 to 55 years-
old) that received 100 mg once daily (QD), 200 mg QD, 400 mg QD, 400 mg twice a day,
and 800 mg QD for 7 days); (iii) a two-part study in subjects aged 65 years and older
with a single 400-mg dose in 15 subjects and a 400-mg QD dosing regimen for 7 days in
12 subjects [89]. FV-100 was shown to be rapidly and extensively converted to CF-1743;
CF-1743 renal excretion was very low; high-fat but not a low-fat meal reduced exposure
to CF-1743; and the FV-100 pharmacokinetic profile was similar in elderly and younger
subjects. All doses maintained mean drug plasma levels of the active form of FV-100 that
exceeded the EC50 for approximately 24 h, supporting the potential for once-a-day dosing
in phase II trials. FV-100 was well tolerated at all doses and no serious adverse events were
reported.
The safety of FV-100 and its efficacy in reducing pain associated with acute HZ
compared to valacyclovir was evaluated in a prospective, multicenter, parallel-group,
double-blind, randomized study [90]. Patients were ≥50 years old, had a diagnosis of
HZ within 72 h of the formation of lesions and presented HZ-associated pain. They were
randomized to receive a 7-day course of either FV-100 200 mg 1× per day (n = 117), FV-100
400 mg 1× per day (n = 116), or valacyclovir 1000 mg 3× per day (n = 117). Burden
of illness (BOI), incidence and duration of clinically significant pain (CSP), pain scores,
incidence and severity of PHN, and times to full lesion crusting and to lesion healing
were used to evaluate efficacy. Safety was evaluated based on adverse event (AE)/ severe
adverse events (SAE) profiles, changes in laboratory and vital signs values, and results of
electrocardiograms. The BOI scores for pain through 30 days were 114.5 (200 mg FV-100),
110.3 (400 mg FV-100), and 118.0 (valacyclovir). The incidences of PHN at 90 days were
17.8%, 12.4%, and 20.2%, respectively, for FV-100 200 mg, FV-100 400 mg, and VACV.
Adverse event and SAE profiles were similar in the two FV-100 and the valacyclovir groups.
Although this trail missed the primary end-point (no statistically significant difference
among the treatment groups for BOI at 30 days), a difference between FV-100 400 mg
and valacyclovir groups was found in the 90 days data (14% reduction). These results
point to a potential effect of FV-100 on subacute and chronic pain and demonstrate the
potential utility of FV-100 as an antiviral for the treatment of shingles, diminishing both
pain burden of the acute episode and incidence and severity of PHN. Reduced incidence
of PHN, the most clinically meaningful endpoint, and reduced use of additional pain
medication (opioids) for the management of PHN in the FV-100 arm vs. valacyclovir arm
was seen. Compared to the standard of care valacyclovir, FV-100 offers secondary benefits
over valacyclovir because FV-100 is once daily dosing vs. valacyclovir three-times dosing.
6.2. Carbocyclic Nucleoside Analogues: H2G (Omaciclovir) and Its Prodrug (Valomaciclovir)
H2G, (R)-9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine, omaciclovir (Figure 3), a
carbocyclic nucleoside analogue, has potent activity against different herpesviruses, being
especially active against VZV, HSV and EBV but lacking activity against HCMV [91]. The
average EC50 for omacyclovir was 2.3 ± 0.8 µM, compared to 46.8 µM for acyclovir and
78.7 µM for penciclovir against 20 VZV clinical isolates, pointing to a superior activity of
omaciclovir against this virus [92].
Omaciclovir has a mode of action similar to that of acyclovir, but with less selectivity as
a substrate for TK and resistance to omaciclovir maps to the TK [93]. However, omaciclovir,
in contrast to acyclovir, is not an obligate chain terminator, although incorporation of the
triphosphate form (omaciclovir-TP) results in limited chain elongation. Omaciclovir-TP has
a longer intracellular half-life than ACV-TP (providing dosing advantages over acyclovir)
and is a potent inhibitor of VZV DNA polymerase though less active than ACV-TP. The anti-
herpesvirus activity of omaciclovir can be markedly enhanced by the immunosuppressive
agent mycophenolate mofetil [94].
Molecules 2021, 26, 1132 17 of 34
Since omaciclovir oral bioavailability is of 17% in cynomolgus monkeys, similar to

that of acyclovir, the diester prodrug valomaciclovir stearate, EPB-348 [L-valine, (3R)-3[2-
amino-1,6-dihydro-6-oxo-purin-9-yl]methyl]-4[(1-oxooctadecyl)oxo]butylester] (Figure 3)
was synthesized with an oral bioavailability of >70% in rats and monkeys, and >60%
in humans [95]. Omaciclovir was licensed from the Swedish biotech company Medivir
AB to Epiphany Biosciences for further development under the name EPB-348. A phase
IIb trial enrolled 373 immunocompetent patients with acute HZ, randomized into three
arms: 1 g 1× daily valomaciclovir stearate, 2 g once daily valomaciclovir stearate, and
1 g 3× per day valacyclovir [96]. Eighteen patients also received 3 g of valomaciclovir
stearate once daily. The primary endpoint was non-inferiority in terms of time to complete
crusting of the shingles rash for the 1× daily valomaciclovir stearate cohort compared to
valacyclovir cohort. Once daily valomaciclovir stearate 2 g met the primary endpoint, being
more convenient than 3× daily valacyclovir for the treatment of HZ and also equally safe.
Valomaciclovir stearate proved non-inferior to VACV in the secondary endpoints (time
to complete pain resolution, time to rash resolution and time to cessation of new lesion
formation). Moreover, the highest valomaciclovir stearate dose (3 g 1× daily) demonstrated
superiority to valacyclovir for the primary endpoint with no significant adverse event
differences between valomaciclovir stearate and valacyclovir groups, being nausea the
most common adverse event in all patient groups.
Valomaciclovir stearate proved also effective against acute infectious mononucleosis
due to primary EBV infection, for which there is no FDA-approved treatment. The findings
of a randomized, placebo-controlled, double-blind trial of valomaciclovir stearate for
infectious mononucleosis were reported in 2009 at a conference but data have not yet been
published [97]. Omaciclovir produced a significant decrease in median EBV load in the
oral compartment compared to placebo but no differences were found in clearance of EBV
DNAemia, CD8:CD4 ratios, CD8 lymphocytosis, or CD8 responses to lytic and latent EBV
tetramers in the valomaciclovir stearate vs. placebo group.
On Epiphany Biosciences’ website, omaciclovir stearate is still listed as active but
without information on further development.
6.3. Brincidofovir
Brincidofovir (CMX001) (Table 2) is an orally bioavailable lipid acyclic nucleoside
phosphonate (ANP) with the same broad-spectrum activity against DNA viruses as its
parent compound cidofovir.
Because of the limitations associated with the use of cidofovir, the hexadecyloxypropyl
(HDP) ester of cidofovir (CMX001, brincidofovir) (Table 2) was synthesized. In alkoxyalkyl
esters prodrugs, a natural fatty acid (lysophosphatidylcholine) molecule is used as carrier
to facilitate drug absorption in the gastrointestinal tract [98,99]. Brincidofovir has improved
uptake and absorption, an oral bioavailability in mice of 88–97% (compared to less than
5% for cidofovir), increased cell penetration (10–20 fold) and higher intracellular levels
(100-fold) of CDV-DP than those reached with cidofovir, resulting in superior antiviral
activity. Furthermore, brincidofovir is not nephrotoxic because, in contrast to cidofovir,
it is not a substrate of the human organic anion transporter 1 enzyme present in the
proximal renal tubular cells. Despite promising preclinical data with brincidofovir, the
results of a phase III trial evaluating its efficacy in the prevention of HCMV disease in
seropositive allogeneic hematopoietic stem cell transplant patients were disappointing
(SUPPRESS trial, NCT01769170) [100]. The end-point of the study was prevention of clinical
significant HCMV infections 24 weeks’ post-transplantation. Unfortunately, a higher
viral infection rate was found in the brincidofovir arm than in the placebo group (22%
vs. 11%) as well as a higher proportion of patients developing graft-versus-host-disease
(GvHD) and digestive symptoms. It is unclear if the emergence of digestive symptoms was
linked to drug toxicity or if the drug favored the onset of digestive GvHD, for which the
patients had to start immunosuppression explaining the increase in clinically significant
HCMV infections. Based on the results of this study, Chimerix suspended further trials
Molecules 2021, 26, 1132 18 of 34
with oral brincidofovir for HCMV. In September 2019, SymBio Pharmaceuticals Limited
(SymBio, Tokyo, Japan) announced an exclusive global license agreement with Chimerix
Inc. for brincidofovir. Chimerix granted SymBio exclusive worldwide rights to develop,
manufacture, and commercialize BCV in all human indications, except for the prevention
and treatment of smallpox.
Regarding the clinical data of brincidofovir against VZV, a retrospective study includ-
ing 30 HSCT recipients, provided limited-evidence on the potential efficacy of brincidofovir
for prophylaxis of HSV and VZV in this group of patients [101]. The successful use of
brincidofovir in management of disseminated acyclovir- and cidofovir-resistant VZV in
a hematopoietic stem cell transplant patient with chronic GvHD who was intolerant to
foscarnet has also been reported [102].
7. Candidate anti-VZV Drugs

7.1. Nucleoside/Nucleotide Analogues
7.1.1. Phenoxazine Derivatives
Phenoxazine [1,3-diaza-2-oxophenoxazine] binds strongly to guanine in a duplex and
improves TT-TT stacking interactions with adjacent bases. The phenoxazine scaffold is com-
monly employed to stabilize nucleic acid duplexes and fluorescent probes incorporating a
phenoxazine component have been used for the study of nucleic acid structure, recognition,
and metabolism. Phenoxazines are well-known in the field of medicinal chemistry because
they have various biological activities, i.e., anticancer, antiviral, antidiabetic, antioxidant,
anti-Alzheimer, anti-inflammatory, and antibiotic properties [103].
The antiviral activity against a panel of diverse viruses of newly synthesized phenoxazine-
based nucleoside derivatives has been recently reported [104]. 3-(20 -Deoxy-β-D-ribofuranosyl)-
1,3-diaza-2-ox-ophenoxazine (compound 7a) (Table 3) proved to be a potent inhibitor of
VZV replication with superior activity against wild-type than TK− strains (EC50 = 0.06 µM
and 10 µM, respectively) [104]. Interestingly, compound 7a was not cytotoxic or cytostatic
for HEL cells at 100 µM (the maximum concentration tested), resulting in selectivity indices
(ratio CC50 /EC50 ) of 1667 (reference Oka strain) and 10 (TK− 07-1). The mechanism of
action of phenoxazines derivatives against VZV is unknown but previously described
Molecules 2021,
Molecules 2021,26,
26,1132
1132 phenoxazine derivatives with antiviral activity against HCMV, HSV-1 and HSV-2, 19 19 of35
were
of 35
shown to directly inactive herpesviruses [105].
Table
Table 3.Candidate
Table3.3. Candidateanti-VZV
Candidate anti‐VZVdrugs.
anti‐VZV drugs.Compounds
drugs. Compoundsdescribed
Compounds describedin
described inthe
in thelast
the lastyears
last yearsshowing
years showingpromising
showing promisingactivity
promising activityagainst
activity againstVZV.
against VZV.
VZV.
EC50 EC50 EC50 EC50 Activity Against
Against Other
Other
EC50 EC50 Activity
Compound
Compound
Compound TK+ TK− CC5050 Activity against Other Human
CC50 CC
TK+ VZV
VZV TK−VZV
VZV Herpesviruses
Human Herpesviruses
TK+
VZV TK−
VZV Human Herpesviruses
Nucleoside/nucleotideanalogues
Nucleoside/nucleotide
Nucleoside/nucleotide analogues
analogues
Phenoxazine derivatives
Phenoxazine derivatives 0.06 μM
0.06 μM 10 μM
10 μM >100 μM
>100 μM No activity
No activity against
against HCMV
HCMV
0.06 µM 10 µM >100 µM No activity against HCMV

Compound 7a
Compound 7a
22′′‐Deoxyribose
‐Deoxyribose emimycine
emimycine nucleosides
nucleosides 0.99 μM
0.99 μM 6.91 μM
6.91 μM >412 μM
>412 μM Activity against
Activity against HSV‐1,
HSV‐1, but
but
lower
lower
Activity activity
activity
against against
against
HSV-1, TK−−
TK
but lower
Compound 27a
27a activity against
HSV‐1 TK − HSV-1
and against
against andNo
HSV‐2.
Compound 0.99 µM 6.91 µM >412 µM HSV‐1 and HSV‐2. No
against HSV-2. No anti-HCMV
anti‐HCMV activity
anti‐HCMV
activity activity
C5‐Substituted‐(1,3‐diyne)‐2‐deoxyuridines
C5‐Substituted‐(1,3‐diyne)‐2‐deoxyuridines ~1 μM
~1 μM >20 μM
>20 μM 55 μM
55 μM Decreased activity
Decreased activity against
against
HSV‐1 TK−− and

HSV‐1 TK and HSV‐2.
HSV‐2.
For compound
For compound 26, 26, RR == p‐
p‐ No anti‐HCMV
No anti‐HCMV activity
activity
(OCF33)C
(OCF )C66H
H44––
Phenoxazinederivatives
Phenoxazine derivatives 0.06μM
0.06 μM 10μM
10 μM >100μM
>100 μM Noactivity
No activityagainst
againstHCMV
HCMV
Compound 7a
Compound 7a
Compound7a
7a
Compound
Molecules 2021, 26, 1132 19 of 34
2′‐Deoxyribose emimycine nucleosides 0.99 μM 6.91 μM >412 μM Activity against HSV‐1, but
2′‐Deoxyribose emimycine
′‐Deoxyriboseemimycine nucleosides 0.99 μM 6.91 μM >412 μM Activity against HSV‐1, but
22′‐Deoxyribose emimycinenucleosides
nucleosides 0.99μM
0.99 μM 6.91μM
6.91 μM >412μM
>412 μM Activity
Activity against
against HSV‐1,
lower activity
HSV‐1, but
against TK
but
−
Table 3. Cont.
Compound 27a
lower
lower
lower
activity
activity
activity
against
against
against
HSV‐1 and against HSV‐2. No
TK
TK
TK −−−
Compound 27a
Compound27a
27a EC50 EC50 HSV‐1
HSV‐1 and against
andagainst
against HSV‐2. No
HSV‐2.No
No
Compound HSV‐1
Activity and
against
anti‐HCMV OtherHSV‐2.
activity Human
Compound TK+ TK− CC50 anti‐HCMV activity
Herpesviruses
anti‐HCMVactivity
VZV VZV
C5‐Substituted‐(1,3‐diyne)‐2‐deoxyuridines ~1 μM >20 μM 55 μM Decreased activity against
C5‐Substituted‐(1,3‐diyne)‐2‐deoxyuridines
C5‐Substituted‐(1,3‐diyne)‐2‐deoxyuridines ~1 μM
~1μM
μM >20 μM
>20μM
μM 55 μM
55μM
μM Decreased activity
activity against
Decreased activity against
C5‐Substituted‐(1,3‐diyne)‐2‐deoxyuridines ~1 >20 55 Decreased
HSV‐1 TK− and HSV‐2.against
HSV‐1
HSV‐1
HSV‐1
TK
TK
− and
TK−−and HSV‐2.
andactivity
HSV‐2.
HSV‐2.
For compound 26, R = p‐ No
Decreasedanti‐HCMV
activity against HSV-1
For compound
Forcompound
compound 26, RR==p‐p‐
26,R ~1 µM >20 µM 55 µM TK−NoNo
and
No anti‐HCMV activity
HSV-2.No activity
anti‐HCMV anti-HCMV
activity
For
(OCF 3)C6H4–
26, = p‐ anti‐HCMV
(OCF 3)C6H4– activity
(OCF3)C
(OCF 3)C6H
6H 4–
4–
Carbocyclic nucleosides: 0.11 μM No data >300 μM Activity against HCMV, no

Carbocyclic nucleosides:
Carbocyclicnucleosides:
nucleosides: 0.11 μM
0.11μM
μM No
No data >300
data>300 μM
>300μM Activity
μM data
Activity against
against HCMV,
HCMV, no no
no
Carbocyclic
3‐Substituted 3‐deaza‐5′‐noraristeromyin derivatives 0.11 No data
available Activity against
on other HCMV,
herpesviruses
3‐deaza‐5′′‐noraristeromyin
3‐Substituted 3‐deaza‐5 ‐noraristeromyin derivatives available data on other herpesviruses
3‐Substituted3‐deaza‐5
3‐Substituted ′‐noraristeromyinderivatives
derivatives available
available dataon
data onother
otherherpesviruses
herpesviruses
No data
In compound 4, X = Br Activity against HCMV, no data
In compound 4,4,XX==Br 0.11 µM avail- >300 µM
InIncompound
compound4, X = BrBr on other herpesviruses
able
Xanthine‐based acyclic nucleoside phosphonates 2.62 μM 4.58 μM 111 μM Activity against HSV‐1, HSV‐
Xanthine‐based acyclic
Xanthine‐basedacyclic nucleoside
acyclicnucleoside
nucleosidephosphonates
phosphonates 2.62 μM
2.62μM
μM 4.58 μM
4.58μM
μM 111 μM
111μM
μM Activity
Activityagainst HSV‐1,
againstHSV‐1, HSV‐
HSV‐1,HSV‐
HSV‐
Xanthine‐based PMEXphosphonates 2.62 4.58 111 2Activity against
and HCMV
PMEX
PMEX 22and HCMV
andHCMV
HCMV
PMEX 2 and
Activity against HSV-1, HSV-2
2.62 µM 4.58 µM 111 µM
and HCMV
Cyclopentyl nucleoside phosphonates 5.35 μM 8.83 μM >289 μM Activity against HSV‐1, HSV‐
Cyclopentyl nucleoside
Cyclopentylnucleoside phosphonates
nucleosidephosphonates
phosphonates 5.35 μM
5.35μM
μM 8.83 μM
8.83μM
μM >289 μM
>289μM Activity
μM 2Activity
Activityagainst HSV‐1,
HSV‐1,HSV‐
HSV‐
Cyclopentyl 5.35 8.83 >289 against
and HCMV
22and HCMV
andHCMV
HCMV
Compound 23 2 and
Compound 23
Compound23
23
Compound
5.35 µM 8.83 µM >289 µM
and HCMV
Nuceoside/nucleotide prodrugs
Molecules 2021, 26, 1132
Nuceoside/nucleotide prodrugs 20 of 35
Nuceoside/nucleotideprodrugs
(E)‐But‐2‐enyl nucleoside phosphonoamidates 0.39 μM 0.33 μM ≥83 μM Activity against HSV‐1, HSV‐
2 and HCMV
For compound 19, Activity against HSV-1, HSV-2
0.39 µM 0.33 µM ≥83 µM
and HCMV
R = Bn
R1 = CH3
Prodrugs
ProdrugsofofC5-substituted
C5‐substitutedpyrimidine acyclic
pyrimidine nucleosides
acyclic nucleosides
Bis(POM) derivative of (E)-TbutP (compound 16)
Bis(POM)derivative
Bis(POM) derivativeofof(E)-5Br-UbutP
(E)‐TbutP (compound
(compound16) 18)
Bis(POM) derivative of (E)‐5Br‐UbutP (compound 18)
R = CH3 (E)‐compound 16 0.41 μM 0.19 μM 35 μM Activity against HSV‐1 &
HSV‐2 and no anti‐HCMV
activity
R = Br (E)‐ compound 18 20 μM 15 μM 35 μM Weak activity against HSV‐1,

HSV‐2, no anti‐HCMV
(E)‐But‐2‐enyl
Molecules
(E)‐But‐2‐enyl nucleoside
2021, 26, 1132
(E)‐But‐2‐enyl nucleoside phosphonoamidates
nucleosidephosphonoamidates
phosphonoamidates 0.39 μM
0.39μM
0.39 μM 0.33 μM
0.33μM
0.33 μM ≥83 μM
≥83μM
≥83 μM Activity against
Activityagainst
Activity against HSV‐1,
20 of 35 HSV‐
HSV‐1,HSV‐
HSV‐1, HSV‐
(E)‐But‐2‐enyl nucleoside phosphonoamidates 0.39 μM 0.33 μM ≥83 μM 22and
and HCMV
andHCMV
HCMV
2Activity against HSV‐1, HSV‐
For
For compound
Forcompound 19,
compound19,
19, 2 andHSV‐1,
HCMV
(E)‐But‐2‐enyl nucleoside phosphonoamidates 0.39 μM 0.33 μM ≥83 μM Activity against HSV‐
RR===Bn
R
For Bn
Bn
compound 19,
Molecules 2021, 26, 1132 2 and HCMV 20 of 34
R1
R1
ForR1
=
=
==BnCH
CH3
CH3 19,
Rcompound 3
R =R1Bn = CH3
Prodrugs
Prodrugsof
Prodrugs of C5‐substituted
ofC5‐substituted
C5‐substituted pyrimidine
pyrimidine
pyrimidine acyclic nucleosides
acyclicnucleosides
acyclic nucleosides
R1 = CH 3 Table 3. Cont.
Bis(POM)
Bis(POM)of
Bis(POM)
Prodrugs derivative
derivative
derivative of
C5‐substituted(E)‐TbutP
ofof(E)‐TbutP
pyrimidine(compound
(compound 16)
16)
acyclic16)
nucleosides
Prodrugs of derivative
C5‐substituted pyrimidine acyclic nucleosides EC50 EC50
Bis(POM)
Bis(POM)derivative
Bis(POM)
Bis(POM) derivativeof
derivative of
of (E)‐5Br‐UbutP
ofCompound
(E)‐5Br‐UbutP
(E)‐5Br‐UbutP
(compound
(compound
(compound 18)
18)
16) 18) Activity against Other Human
TK+ TK− CC50
Bis(POM) derivative of (E)‐TbutP (compound 16) Herpesviruses
RRR===CH
CH
Bis(POM) derivative of (E)‐5Br‐UbutP (E)‐compound
CH333(E)‐compound
(E)‐compound
(compound 16
1618)
16 0.41
VZV μM
μM VZV
0.41μM
0.41 0.19 μM
0.19μM
0.19 35
μM 35 μM
35μM
μM Activity against
Activity against
Activity HSV‐1
against HSV‐1 &
HSV‐1 &&
Bis(POM) derivative of (E)‐5Br‐UbutP (compound 18)
R = CH3 (E)‐compound 16 0.41 μM 0.19 μM 35 μM HSV‐2
HSV‐2 and
HSV‐2
Activity and
and no
no
against anti‐HCMV
no anti‐HCMV
anti‐HCMV
HSV‐1 &
R = CH3 (E)‐compound 16 0.41 μM 0.19 μM 35 μM Activity against HSV‐1 &
activity
activity and no anti‐HCMV
activity
HSV‐2
HSV‐2 Activity
and no against HSV-1 & HSV-2
anti‐HCMV
0.41 µM 0.19 µM 35 µM
activity and no anti-HCMV
activity activity
RRR===Br
Br (E)‐
Br(E)‐ compound
(E)‐compound 18
compound18
18 20 μM
20μM
20 μM 15 μM
15μM
15 μM 35 μM
Weak
35μM
35 μM activity
Weakactivity
Weak against
activityagainst HSV‐1,
againstHSV‐1,
HSV‐1,
RR==Br
Br(E)‐
(E)‐compound 18 18
compound 20 μM 20 μM
15 μM 15 μM
35 μM 35Weak HSV‐2,
HSV‐2,
μM activity
Weakagainst
HSV‐2, no
HSV‐1,
no
activity anti‐HCMV
no against
anti‐HCMV
anti‐HCMV
HSV‐1,
Weak activity against HSV-1,
R = Br (E)- compound 18 20 µM 15 µM 35 µM
HSV‐2, HSV-2,
no no
activity
activity
HSV‐2, anti-HCMV
anti‐HCMV
activity no activity
anti‐HCMV
In
In compound
Incompound 15,
15,XXX===Me,
compound15, Me,
Me, 0.5 μM
0.5μM
0.5 μM 0.09 μM
0.09μM
0.09 μM 40
40
40 μM
activity
μM
Activityagainst
Activity
activity HSV‐1,
HSV‐1,HSV‐
HSV‐
In R
compound 15, X
1 = Neopent = Me,
and Ar = naphtol 0.5 μM 0.09 μM 40 μM Activity against
2 andHSV‐1,
HCMV HSV‐
RR1 1=compound
In =Neopent
Neopentand
andX
15, Ar
Ar =naphtol
naphtol
= =Me, 0.5 μM 0.09 μM 40 μM 2and
andHCMV
HCMV
R1 = Neopent and Ar = naphtol 2 and HCMV
R1 = Neopent and Ar = naphtol 2 andagainst
Activity HCMVHSV-1, HSV-2
0.5 µM 0.09 µM 40 µM
and HCMV
In
In In compound
Incompound
compound
compound 21,
21,
21, X21, XXX===RMe,
= Me, Me,
Me, RRR111===Neopent
1 = Neopent
Neopent
Neopent 0.47
0.47 μM0.47 μM
0.470.20
μM 0.20
μMμM 0.20
0.20 μM
μM
μM
>100 >100
>100
μM >100 μM Activity
μM against
μM
Activity Activity
Activity against
against
against
HSV‐1, HSV‐1, HSV‐
HSV‐1,HSV‐
HSV‐HSV‐1, HSV‐
In compound 21, X = Me, R1 = Neopent 0.47 μM 0.20 μM 2 and
>100 μMHCMV22and
and HCMV
andHCMV
HCMV
2 andagainst
Activity HCMVHSV-1, HSV-2
0.47 µM 0.20 µM >100 µM
and HCMV
Prodrugs of pyrimidine acyclic nucleoside analogues

Prodrugs
Prodrugs of
of
Prodrugsof pyrimidine
pyrimidine
ofpyrimidine acyclic
acyclic
pyrimidineacyclic nucleoside
nucleosideanalogues
nucleoside
acyclicnucleoside analogues
analogues
Prodrugs analogues
Parent compound PMEO‐DAPy 2.07 μM 4.72 μM 90.3 μM Activity against HSV‐1 &
Parent
Prodrugs of pyrimidine acyclic
Parent compound
Parentnucleoside
compound
compound PMEO‐DAPy
PMEO‐DAPy
analogues
PMEO‐DAPy 2.07
2.07 μM
2.07μM
μM 4.72 4.72 μM
4.72μM
μM 90.3 90.3
90.3 μM Activity
μMbut not
μM Activity
Activity against HSV‐1
against HSV‐1 &
HSV‐1 &&
HSV‐2 against against
HCMV
Activity against HSV-1 & HSV-2
Parent compound PMEO‐DAPy 2.07 µM
2.07 μM 4.72 µM
4.72 μM 90.3 µM HSV‐2
HSV‐2
90.3 μM butHSV‐2
Activitybut
but not
not
not against
butagainst
against
against HCMV
HCMV
HCMV
HSV‐1 &
not against HCMV
Bis(POC)‐PMEO‐DAPy 0.32 μM 0.29 μM 15.1 μM Activity against HSV‐1
HSV‐2 but &
not against HCMV
Bis(POC)‐PMEO‐DAPy
(Compound 4)
Bis(POC)‐PMEO‐DAPy
Bis(POC)‐PMEO‐DAPy 0.32 μM
0.32μM
0.32 μM 0.29 μM
0.29μM
0.29 μM 15.1 μM
HSV‐2
15.1μM
15.1 and Activity
marginal
activity
Activity against HSV‐1
against HSV‐1
HSV‐1 & &
&
(Compound
(Compound 4)
(Compound4)
4)
Bis(POC)‐PMEO‐DAPy 0.32 μM 0.29 μM against HCMV
15.1 μM HSV‐2
HSV‐2
Activity and
HSV‐2 andand marginal
marginal
marginal
against activity
HSV‐1activity
activity
&
(Compound 4) against
Activity
against
HSV‐2 HCMV
against
against HCMV
HCMV
and HSV-1 & HSV-2
marginal activity
0.32 µM 0.29 µM 15.1 µM and marginal activity against
against HCMV
HCMV
Molecules 2021, 26, 1132 21 of 35
Bis(aminoacid) 0.56 μM 1.69 μM 25.9 μM Activity against HSV‐1 &

Phosphoramidate HSV‐2against
Activity and HSV-1
low & HSV-2
activity
0.56 µM 1.69 µM 25.9 µM
(Compound 5) andagainst
low activity
HCMV against HCMV
Parent compound PME‐5azaC 100 μM 40 μM >200 μM Marginal activity against

HSV‐1,activity
Marginal HSV‐2 against
& HCMVHSV-1,
100 µM 40 µM >200 µM
HSV-2 & HCMV
0.32 μM 0.79 μM 79.2 μM Activity against HSV‐1, HSV‐

Mono‐octadecyloxyethyl‐ 2 and HCMV
PME‐5‐azaC (Compound 17)
Diamyl aspartate amidate prodrugs of 3‐Fluoro‐2‐

Molecules
Molecules2021,
2021,26,
26,1132
1132 21
21of
of35
35
Bis(aminoacid) 0.56 μM 1.69 μM 25.9 μM Activity against HSV‐1 &
Phosphoramidate HSV‐2 and low activity
Bis(aminoacid)
Bis(aminoacid) 0.56
0.56μM
μM 1.69
1.69μM
μM 25.9
25.9μM
μM Activity
Activity against
against HSV‐1
HSV‐1 &
&
(Compound 5) against HCMV
Molecules 2021, 26, 1132 Phosphoramidate
Phosphoramidate HSV‐2
HSV‐2 and
and low
low activity
activity 21 of 34
(Compound
(Compound5)
5) against
againstHCMV
HCMV
Parent compound PME‐5azaC 100 μM 40 μM >200 μM Marginal activity against
Parent
Parentcompound
compoundPME‐5azaC
PME‐5azaC 100
100 μM 3. Cont.
Table
μM 40
40μM
μM >200
>200μM
μM Marginal HSV‐1,
Marginal activityHSV‐2
activity & HCMV
against
against
HSV‐1, HSV‐2 & HCMV
HSV‐1, HSV‐2 & HCMV
EC50 EC50
Activity against Other Human
Compound TK+ TK− CC50
Herpesviruses
VZV VZV
0.32 μM 0.79 μM 79.2 μM Activity against HSV‐1, HSV‐
0.32
0.32μM 0.79
0.79μM 79.2
79.2μM Activity
Activity against
Mono‐octadecyloxyethyl‐ μM μM μM 2 andHSV‐1,
against HSV‐1,
HCMV
2 and HCMV
HSV‐
HSV‐
Mono‐octadecyloxyethyl‐
Mono‐octadecyloxyethyl‐ 22and
andHCMV
HCMV
PME‐5‐azaC (Compound 17)0.32 µM 0.79 µM 79.2 µM
PME‐5‐azaC
PME‐5‐azaC(Compound
(Compound17)
17) and HCMV
Diamyl aspartate amidate prodrugs of 3‐Fluoro‐2‐

Diamyl
Diamylaspartate
aspartateamidate
amidateprodrugs
prodrugsof
of3‐Fluoro‐2‐
3‐Fluoro‐2‐
(phosphonomethoxy)propyl acyclic
(phosphonomethoxy)propyl nucleoside
(phosphonomethoxy)propylacyclic
acyclicnucleoside
nucleoside
phosphonates
phosphonates
phosphonates
BaseBase
Base adenine:
adenine:
adenine: (S) (S)(R)
(S)22a,
22a, 22a,
(R) 22b(R) 22b
22b
Base cytosine:
BaseBase (S)
(S)23a,
cytosine:
cytosine: (S)(R)
23a, 23b
23a,
(R) 23b(R) 23b
Base cytosine:
BaseBase
cytosine: (S)
(S)25a,
cytosine: (S)(R)
25a, (R) 25b
25b(R) 25b
25a,
0.057
22a
22a
22a 0.05 0.05
μM µM
0.05μM 0.057 μM
μM 1.96
0.057µM 1.96 µM
1.96μM
μM No No selectivity
Noselectivity
selectivity against against HCMV
againstHCMV
HCMV
22a 0.05 μM 0.057 μM 1.96 μM No selectivity against HCMV
23a
23a 3.15
3.15μM
μM 1.32
1.32μM
μM 74.7
74.7μM
μM Activity
Activity and
and andselectivity
Activity selectivity
selectivity against
23a
23a 3.15
3.15 µMμM 1.321.32µM μM74.7 µM
74.7 μM Activity and selectivity
againstHCMV
against HCMV
HCMV
against HCMV
25a
25a 0.59
0.59μM
μM 0.079 μM
μM 27.8
0.0790.079 27.8μM
μM Activity
Activity but
but low
low selectivity
selectivity
25a
25a 0.59 µM 27.8
0.59 μM µM 0.079 μM 27.8 µM μM Activity but low
Activity butselectivity
low selectivity
25a
25b
25b 0.89
0.89μM
μM 0.11 0.11μM
μM 10.2 μM against
10.2μM HCMV
againstagainst
HCMV HCMV
25b 0.89 μM 0.110.11 against HCMV
25b
(S)‐cHPMPA
(S)‐cHPMPA Phosphonamidates
Phosphonamidates 0.89
0.00045
0.00045 µM
0.00054
0.00054 12μM
µM
12 μM
μM 10.2
10.2 µM μM against
Activity
Activity againstHSV‐1,
HSV‐1,HSV‐2,
HSV‐2,
(S)‐cHPMPA Phosphonamidates μM
μM 0.00045
μM
μM 0.00054 12and
μMHCMV
and HCMVActivity against HSV‐1, HSV‐2,
In (S)-Ile-cHPMPA
In (S)-Ile-cHPMPA μM μM and HCMV
In (S)-Ile-cHPMPA
(compound
(compound 16),
16),RR ==
0.00045 0.00054 Activity against HSV-1, HSV-2,
(compound 16), R = 12 µM
µM µM and HCMV
Non‐nucleoside
Non‐nucleosideanalogues
analogues
Pyrazolo[1,5−c]1,3,5‐triazin‐4‐one
Non‐nucleoside analogues (35B2)
Pyrazolo[1,5−c]1,3,5‐triazin‐4‐one (35B2) 0.75
0.75μM
μM 4.6
4.6μM
μM 152.5
152.5μM
μM Weak
Weak activity
activity against
against HSV‐1,
HSV‐1,
Non-nucleoside analogues
no
noanti‐HCMV
anti‐HCMVactivity
activity
Pyrazolo[1,5−c]1,3,5‐triazin‐4‐one (35B2) 0.75 μM 4.6 μM 152.5 μM Weak activity against HSV‐1,
no anti‐HCMV activity
Weak activity against HSV-1, no
0.75 µM 4.6 µM 152.5 µM
anti-HCMV activity
Molecules 2021, 26, 1132 22 of 35
[(5‐Chlorobenzo[b]thiophen‐3‐yl)methyl] [(4‐chloro‐ 16.9 μM 18.3 μM >100 μM

phenyl)sulfonyl]amine (45B5)
16.9 µM 18.3 µM >100 µM No No
data data available
available on otheronviruses
other
viruses
N‐(4‐Chlorophenyl)‐5‐nitro‐3‐thienylcarboxamide (133G4) 19.3 μM No data 537 μM Activity against HCMV

available
Indole‐based derivatives 2.6 μM 2.0 μM >100 μM No activity against HSV‐1,

Molecules 2021, 26, 1132 22 of 35
[(5‐Chlorobenzo[b]thiophen‐3‐yl)methyl]
[(5‐Chlorobenzo[b]thiophen‐3‐yl)methyl] [(4‐chloro‐
[(4‐chloro‐ 16.9 μM
16.9 μM 18.3 μM
18.3 μM >100 μM
>100 μM
Molecules 2021, 26, 1132 22 of 35
phenyl)sulfonyl]amine(45B5)(45B5)
[(5‐Chlorobenzo[b]thiophen‐3‐yl)methyl] [(4‐chloro‐
phenyl)sulfonyl]amine [(4‐chloro‐ 16.9 μM
16.9 μM 18.3 μM
18.3 μM >100 μM
>100 μM
phenyl)sulfonyl]amine (45B5) [(4‐chloro‐ 16.9 μM 18.3 μM >100 No No data
μM data available
available on other
on other
Molecules 2021, 26, 1132 22 of 34
phenyl)sulfonyl]amine (45B5) Noviruses
Nodata
viruses dataavailable
availableononother
other
[(5‐Chlorobenzo[b]thiophen‐3‐yl)methyl] [(4‐chloro‐ 16.9 μM 18.3 μM >100 μM
No data available on other
viruses
viruses
viruses
Table 3. Cont. No data available on other
N‐(4‐Chlorophenyl)‐5‐nitro‐3‐thienylcarboxamide (133G4)
N‐(4‐Chlorophenyl)‐5‐nitro‐3‐thienylcarboxamide (133G4) 19.3 μM 19.3 μMNo No data
data 537 μM537 μM Activity against
Activity against HCMV HCMV
viruses
N‐(4‐Chlorophenyl)‐5‐nitro‐3‐thienylcarboxamide (133G4) EC EC
available
N‐(4‐Chlorophenyl)‐5‐nitro‐3‐thienylcarboxamide (133G4) 19.3 μM
19.350
μM NoNo50 data
available 537537
data μM μM Activity against
Activity
Activity HCMV
against
against HCMV
Other Human
Compound TK+ TK− CC50
N‐(4‐Chlorophenyl)‐5‐nitro‐3‐thienylcarboxamide (133G4) VZV19.3 μM available
No data 537 μM Herpesviruses
Activity against HCMV
available
VZV
available
N‐(4‐Chlorophenyl)‐5‐nitro‐3‐thienylcarboxamide (133G4) 19.3 μM No data 537 μM Activity against HCMV
Noavailable
data
19.3 µM avail- 537 µM Activity against HCMV
Indole‐based derivatives able
2.6 μM2.0 μM2.0 μM >100 μM No activity against HSV‐1,
Indole‐based derivatives 2.6 μM >100 μM No activity against HSV‐1,
Indole‐based derivatives
Indole‐based derivatives 2.62.6
μM μM 2.02.0μMμM >100 μM
>100 μM NoHSV‐2, HSV‐2,
activity
No HCMV
against
activity
HCMV HSV‐1,
against HSV‐1,
Indole‐based derivatives 2.6 μM 2.0 μM >100 μM NoHSV‐2,
activity
HSV‐2, against
HCMVHSV‐1,
HCMV
HSV‐2, HCMV
Indole‐based derivatives 2.6 μM 2.0 μM >100 μM No activity against HSV‐1,
17a 17a No activity against HSV-1, HSV-2,
2.6 µM 2.0 µM >100 µM HSV‐2, HCMV
HCMV
17a
17a
Cephalotaxine
Cephalotaxine esters
17a
esters
17a
Cephalotaxine esters 16.15 16.15 45.82 45.82
ng/mL ng/mL
16.15
16.15 ng/mL ng/mL
45.82
45.82
16.15 45.82 No data
No data available
available on other
on other
Cephalotaxine esters (HT)
(HT)ng/mL16.15
ng/mL (HT) (HT)
45.82
ng/mL
ng/mL
ng/mL No data ng/mL Noviruses—Low selectivity for
No data Nodata
viruses—Lowdataavailable
availableonon
selectivity other
for other
9.96
9.96(HT)
(HT) ng/mL
(HT) 74.71
(HT)
(HT)
74.71 ng/mL No data available on other
(HT)
16.15 No data
NoNo data74.7145.82 VZV
data VZV
No data available
viruses—Low
viruses—Low on for
selectivity
selectivity other
for
9.96
ng/mL
(HT) (HT) viruses—Low selectivity for VZV
ng/mL
9.96
ng/mL 9.96 74.71
ng/mL 74.71
ng/mL
ng/mL No datang/mL ng/mL VZV viruses—Low
VZV selectivity for
(HTT)
ng/mL
(HTT)
(HTT) 9.96
ng/mL (HTT)
74.71
ng/mL
(HTT)
(HTT) ng/mL No data available on other
(HT) (HT) VZV
(HTT)ng/mL
(HTT) No data (HTT)ng/mL
(HTT) viruses—Low selectivity for
HT HT HTTHTTHTT 9.96 74.71
HT
(HTT) (HTT) VZV
Hybrid
HT
Hybrid
HT molecules
molecules HTTHTT ng/mL ng/mL
Hybrid molecules
HT
Hybrid molecules HTThybrid
Dihydropyrimidinone/1,2,3‐triazole
Hybrid molecules
Dihydropyrimidinone/1,2,3-triazole
Dihydropyrimidinone/1,2,3‐triazole hybridhybridmolecules
molecules
molecules (HTT) (HTT)
Hybrid molecules
Dihydropyrimidinone/1,2,3‐triazole hybrid molecules
Dihydropyrimidinone/1,2,3‐triazole
HT HTThybrid molecules
Dihydropyrimidinone/1,2,3‐triazole hybrid molecules
Hybrid molecules 3.62 μM7.85
7.85 μM >100
3.62 3.62μM µM7.85 μM
µM >100
>100 µM μM
μM
Dihydropyrimidinone/1,2,3‐triazole hybrid molecules (8a)
(8a) (8a)
(8a) (8a)(8a)
(8a)3.623.62 μM μM
(8a)7.85
7.85 μMμM
(8a)>100
>100 μM
μMNoNo
anti-HCMV activity
11.33 10.79 anti‐HCMV
>100 µM No anti‐HCMV activity
activity
11.33
(8a)
11.33µM 3.62
(8a)
μM μM
μM 10.79
(8a)7.85
µM(8a)
(7d)10.79 μM μM
μM
(7d) >100 >100
(8a)>100
(7d)(8a)
μM μM
μM
NoNoanti‐HCMV
activity
(7d)
(7d)11.33(8a)μM
11.33 (7d)
μM (7d)
(8a)μM
10.79
10.79 (7d)
μM (7d)
>100(8a)μM
>100 μM
3.62 μM 7.85 μM >100 μM No anti‐HCMV activity
(7d) 11.33 μM
(7d) (7d)10.79 μM
(7d) (7d)>100 μM
(7d)
(8a) (8a) (8a)
(7d) (7d) (7d) No anti‐HCMV activity
8a 7.1.2. 20 -Deoxyribose Emimycin 11.33Nucleosides
μM 10.79 μM >100 μM
8a 7d 7d
8a8a 7d7d Emimycin (1,2-dihydro-2-oxopyrazine(7d) (7d) 4-oxide) (7d)is a pyrazine analogue structurally
8a 7.1.2.7.1.2. 2′‐Deoxyribose
resembling
2′‐Deoxyribose
7d uracil with
Emimycin Emimycin
known Nucleosides properties. Emimycin, its 5-substituted con-
antibacterial
Nucleosides
geners
7.1.2. and
Emimycin the
2′‐Deoxyribose
Emimycin
7.1.2. 2′‐Deoxyribose ribonucleoside
Emimycin
(1,2‐dihydro‐2‐oxopyrazine
Emimycin derivatives
Nucleosides
Nucleosides are devoid
4‐oxide)
4‐oxide) is aofpyrazine
is a pyrazine antiviral activity
analogue
analogue against RNA
structurally
structurally
viruses. Interestingly, some of the 2 0 -deoxyribosyl emimycin derivatives proved potent
8a resembling
7d
resembling uracil
Emimycin
7.1.2. uracil
with
2′‐Deoxyribose with
known known antibacterial
antibacterial
Emimycin properties.
properties.
Nucleosides 4‐oxide) Emimycin,
Emimycin,
is is
a pyrazine its 5‐substituted
its analogue
5‐substituted con‐ con‐
structurally
Emimycin
inhibitors of the (1,2‐dihydro‐2‐oxopyrazine
replication of HSV and VZV 4‐oxide)
but were a pyrazine
completely analogue
devoid of structurally
activity against
genersgeners
resembling and
andEmimycin the
theuracil ribonucleoside
ribonucleoside
with known derivatives
derivatives
antibacterial are
are devoid devoid of antiviral
of antiviral
properties. Emimycin, activity
activity
itsits againstagainst
5‐substituted RNA RNA
con‐
resembling
HCMV [106]. uracil
The with
2 known antibacterial
0 -deoxyribonucleosides properties.
with4‐oxide)
an is Emimycin,
emimycina pyrazine 5‐substituted
analogue
nucleobase con‐
structurally
(structurally sim-
viruses.
viruses.7.1.2.
geners and Interestingly,
2′‐Deoxyribose
Interestingly,
thethe some some
Emimycin
ribonucleoside of
ofknown the 2′‐deoxyribosyl
Nucleosides
the derivatives
2′‐deoxyribosyl areare emimycin
emimycin
devoid of of derivatives
derivatives
antiviral proved
activity proved
potent
against potent
RNA
geners and
resembling
ilar to uracil) uracilribonucleoside
did not with derivatives
antibacterial
display inhibitory activity devoid
properties.
against antiviral
Emimycin,
VZV,completely activity
its
HSV-1 anddevoid against
5‐substituted
HSV-2. of RNAcon‐
In contrast,
inhibitors
inhibitors
viruses. of the of the
Interestingly,
Emimycin replication
replication someof of
HSVof HSV
and
thethe and
VZV butVZV
2′‐deoxyribosyl
(1,2‐dihydro‐2‐oxopyrazine but
were
4‐oxide) were
completely
emimycin
is of devoid
derivatives
a pyrazine ofproved activity
activity
proved
analogue potent
structurally
viruses.
geners Interestingly,
and the some
ribonucleoside of 2′‐deoxyribosyl
derivatives are emimycin
devoid
the presence of 5-methylemimycin (related to the natural thymidine nucleobase) in com- derivatives
antiviral activity against potent
RNA
inhibitors
resembling
inhibitors
viruses. ofInterestingly,
the
of thereplication
uracil withsome
replication of of
known HSV
of the and
antibacterial
HSV and VZV
VZV
2′‐deoxyribosylbutbutwere
properties.
were completely
Emimycin,
emimycin completely devoid
its of of
activity
5‐substituted
devoid
derivatives con‐
activity
pound 27a (Table 3) conferred potent antiviral activity against VZV TK+ (ECproved potent
50 = 0.99 µM)
geners
inhibitorsand the
of the ribonucleoside
replication derivatives are devoid of antiviral activity
of HSV and VZV but were completely devoid of activity against RNA
and HSV-1 TK+ (EC 50 = 1.79 µM), with selectivity indices (ratio CC50 /EC50 ) of 416 and 230,
viruses. Interestingly,
respectively. Compoundsome of the
27a was 2′‐deoxyribosyl
7-fold emimycin
(VZV) and 30-fold derivatives
(HSV-1) less active proved potent
when tested
inhibitors of the replication of HSV and VZV but were
against mutant TK–strains and was devoid of anti-HCMV activity. The 5-ethylemimycin completely devoid of activity
20 -deoxyribose congener 28a has a very similar profile as its 5-methyl congener 27a, but its
antiviral activity is less pronounced.
Molecules 2021, 26, 1132 23 of 34
7.1.3. C5-substituted-(1,3-diyne)-2-deoxyuridines
C5-substituted pyrimidine nucleosides, in particular those in the 20 -deoxyuridine
series, constitute a unique class of compounds, playing an important role as compo-
nents of nucleotide-derived tools for molecular genetics and as antiviral and anticancer
agents. For instance, significant efforts have been expended to develop C5-substituted
analogues that can be incorporated into DNA by viral DNA polymerases, such as the 5-(2-
substituted vinyl)-20 -deoxyuridines, including brivudine. Novel C5-substituted-(1,3-diyne)-
20 -deoxyuridines (with cyclopropyl, hydroxymethyl, methylcyclopentane, p-(substituted)
phenyl and disubstituted-phenyl substituents) have been synthesized and evaluated
against several herpesviruses [107]. The compound 5-[4-(4-trifluoromethoxyphenyl)buta-
1,3-diynyl]-2-deoxyuridine (26, Table 3) emerged as the most potent inhibitor of this series
against VZV with an EC50 of ∼1 µM and a CC50 of 55 µM. This compound had similar
activity as acyclovir but it was less active than brivudine against the VZV TK+ YS and OKA
strains and lost potency against TK− VZV strains (EC50 > 20µM). Compound 26 displayed
moderate activity against HSV-1, HSV-2 and HSV-1 TK− with EC50 values of ~10–15 µM.
7.1.4. Carbocyclic Nucleosides: C-3 halo and 3-methyl substituted

50 -nor-3-deazaaristeromycins
To expand on the antiviral properties of the carbocyclic nucleoside analogue 50 -
noraristeromycin, 3-substituted 3-deaza-50 -noraristeromyin derivatives (i.e., bromo, iodo,
chloro, and methyl) were synthesized [108]. An extensive characterization of their antiviral
activities showed compound 4 (the bromo congener, Table 3) was most favorable towards
the herpesviruses HCMV (EC50 = 1.7 µM), VZV (EC50 = 0.11 µM) without inhibiting cell
growth at a concentration of 300 µM. This compound was also able to inhibit the replication
of hepatitis B virus (HBV) and vaccinia virus but the activity against HSV was not reported.
7.1.5. Xanthine-Based Acyclic Nucleoside Phosphonates (ANPs)

Noncanonic xanthine nucleotides XMP/dXMP play an important role in the balance
and maintenance of intracellular purine nucleotide pool as well as in potential mutage-
nesis. A series of ANPs bearing a xanthine nucleobase were synthesized and evaluated
for their activity against a wide range of DNA and RNA viruses [109]. Within this se-
ries, two ANPs, i.e., 9-[2-(phosphonomethoxy)ethyl]xanthine (PMEX) and 9-[3-hydroxy-2-
(phosphonomethoxy)-propyl]xanthine (HPMPX), showed activity against several human
herpesviruses. PMEX (Table 3), a xanthine analogue of adefovir (PMEA), emerged as the
most important compound, exhibiting also activity against VZV (EC50 = 2.62 µM, TK+ Oka
strain and EC50 = 4.58 µM, TK− 07-1 strain). The (S)HPMPX was less active with EC50
values of 22.7 µM and 17.1 µM, for respectively, TK+ and TK− VZV strains. The hexade-
cyloxypropyl monoester prodrug of PMEX (i.e., HDP-PMEX) proved 7- to 26-fold more
active than the parent compound PMEX against VZV, although a concomitant increase in
its cytostatic activity of 11-fold was also observed indicating successful increase in the cell
uptake. The structures of HPMPX and HDP-PMEX are not reported here but can be found
in the original study by Baszczynski and coworkers [109].
An increase in the EC50 of PMEX of the same magnitude as that measured for adefovir
was found for well-characterized HSV-1 DNA polymerase mutant viruses indicating that
the target of action of the active form of PMEX (i.e., PMEXpp) is the herpesvirus DNA
polymerase. Furthermore, when the inhibitory activity of PMEXpp, was evaluated in
an enzymatic assay against VZV DNA polymerase compared to cellular (α and β) DNA
polymerases, PMEXpp proved inhibitory to VZV DNA polymerase when dGTP was used
as competitive radiolabeled substrate with an IC50 = 7.4 µM without inhibition towards
cellular DNA polymerases.
7.1.6. Cyclopentyl Nucleoside Phosphonates

Both 20 -hydroxy-30 -deoxy- and 20 -deoxy-30 -hydroxycyclopentyl nucleoside phospho-
nates with the natural nucleobases adenine, thymine, cytosine and guanine were synthe-
Molecules 2021, 26, 1132 24 of 34
sized and evaluated for activity against several herpesviruses [110]. The guanine containing
analogues displayed antiviral activity; in particular, the 30 -deoxy congener 23 (Table 3)
was active, with an EC50 of 5.35 µM against TK+ VZV strain and an EC50 of 8.83 µM
against TK− VZV strain, while lacking cytotoxicity (CC50 > 289 µM). The application of
phosphonodiamidate prodrug strategy did not result in a boost in antiviral activity.
7.1.7. (E)-but-2-enyl Nucleoside Phosphonoamidates

A significant amount of research and development on aryl phosphoramidate prodrugs
has been carried out by McGuigan’s group. However, the development of aryl phospho-
noamidates, in particular in the field of ANPs, has been poorly investigated. Recently, the
synthesis and antiviral evaluation of hitherto unknown (E)-but-2-enyl nucleosidephospho-
noamidates using the cross-metathesis in water-under ultrasound irradiation has been
reported by Agrofolio’s group [111]. The overall yield obtained was high, well above the
previously data for the preparation of phosphonoamidates (15% vs. ~3%). Among the syn-
thesized (E)-but-2-enylnucleoside phosphonoamidates, the thymine analogue 19 (Table 3)
proved to be the best prodrug tested against VZV with an EC50 ’s of 0.39 and 0.33 µM for
TK+ and TK− strains, respectively, and a selectivity index ≥200. This innovative synthetic
approach may open the way for the synthesis of new purine and pyrimidine (E)-but-2-enyl
phosphonoamidates.
7.1.8. Prodrugs of C5-Substituted Pyrimidine Acyclic Nucleosides for Antiviral Therapy

While C5-Substituted-Uracil ANPs were devoid of antiviral activity, the bis(POM)
prodrug of (E)-TbutP (compound 16) (Table 3) presented a potent anti-herpesvirus activity,
namely, HSV-1, HSV-2 and VZV (EC50 = 2.5−6.1 µM for these three viruses) [112]. Interest-
ingly, the compound showed a decreased inhibitory effect (EC50 = 9.2 µM) against the TK−
HSV-1 strain, but an increase in activity against the VZV TK− strain with EC50 = 0.19 µM
compared to EC50 = 0.41 µM for VZV TK+ strain. There was no activity against HCMV.
The (E)-bis(POM)-5Br-UbutP congener 18 proved weakly inhibitory against HSV-1, HSV-2,
and VZV with EC50 ’s = 16−33 µM, and of 15–20 µM for VZV) but not against HCMV and
kept activity against TK− HSV-1 and VZV strains. The compounds showed no cytotoxic
at 200 µM, but were slightly cytostatic at ~35 µM for HEL cells. In contrast with the (E)
isomer of bis(POM)-TbutP and bis(POM)-UbutP, the corresponding (Z) isomers exhibited
negligible or no antiviral activity.
The phosphoro(no)amidate approach proved very successful both on nucleoside
analogues (e.g., Sofosbuvir for hepatitis C virus) as well as on ANPs (e.g., Tenofovir
alafenamide for HIV infection and HBV). Excellent results using the phosphoroamidate
approach on adefovir were also obtained. In search for more potent and safe ANPs, the im-
pact of the phosphonoamidate and phosphonodiamidate prodrugs on the antiviral activity
of C5-pyrimidine acyclic nucleosides derivatives functionalized with but-2-enyl- chain was
studied [113]. In the phosphonoamidate series, the most active compound 15 showed sub-
micromolar activity against VZV (EC50 = 0.09–0.5 µM) and µM activity against HCMV and
HSV. Notably, the phosphonodiamidate 21 showed excellent activity against wild type and
TK− VZV strains (EC50 = 0.47 and 0.2 µM, respectively) and HCMV (EC50 = 3.5–7.2 µM)
without cytostatic effect at the highest tested concentration (CC50 > 100).
7.1.9. Prodrugs of the Pyrimidine Acyclic Nucleoside Phosphonates PMEO-DAPy and

PME-5-azaC
Novel prodrugs of 2,4-diamino-6-[2-(phosphonomethoxy)ethoxy]pyrimidine (PMEO-
DAPy) and 1-[2-(phosphonomethoxy)ethyl]-5-azacytosine (PME-5-azaC) prodrugs were syn-
thesized with a pro-moiety consisting of carbonyloxymethyl esters (POM, POC), alkoxyalkyl
esters, amino acid phosphoramidates and/or tyrosine (Table 3) [114]. PMEO-DAPy be-
longs to the class of open-ring ANPs, which are characterized by the phosphonomethoxy
group containing an aliphatic part linked to the position 6 of 2,4-diaminopyrimidine via the
oxygen atom. They are mimics of the appropriate 2,6-diaminopurine derivatives with an
open imidazole ring. Interestingly, PMEO-DAPy has activity against retroviruses, HBV as
Molecules 2021, 26, 1132 25 of 34
well as herpesviruses. The replication of herpesvirus was inhibited by the bis(POC) and the
bis(amino acid) phosphoramidate prodrugs of PMEO-DAPy with lower EC50 values than
those for the parent compound PMEO-DAPy though the selectivity against HSV and VZV
was only slightly improved. Thus, the VZV EC50 values and CC50 values for PMEO-DAPy
were respectively, of 2.07–4.72 µM and 90.3 µM vs. ~0.3 µM and 15.1 µM [Bis(POC), com-
pound 4] and 0.56–1.69 µM and 25.9 µM [bis(amino acid) phosphoramidate, compound 5].
The PME-5-azaC mono-octadecyl ester (compound 17) was the most effective and selective
PME-5-azaC prodrug when evaluated against HSV (EC50 of 0.15–0.35 µM), VZV (EC50 ’s of
0.32–0.79 µM) and HCMV (EC50 ’s of 0.24–1.12 µM) compared to a minimal anti-herpesvirus
activity of the parent compound PME-5-azaC. Although the bis(hexadecylamido-L-tyrosyl)
and the bis(POM) esters of PME-5-azaC proved to be very potent anti-herpesvirus com-
pounds, their selectivity indices were reduced relative to the mono-octadecyl ester prodrug.
7.1.10. Diamyl Aspartate Amidate Prodrugs of 3-Fluoro-2-(phosphonomethoxy)propyl

Acyclic Nucleoside Phosphonates
Acyclic nucleosides bearing a 3-fluoro-2-(phosphonomethoxy)propyl (FPMP) side
chain have moderate anti-HIV efficacy but are devoid of activity against DNA viruses.
Two enantiomeric series of FPMP nucleosides bearing the four natural nucleobases was
recently synthesized [115] (Table 3). Conversion of the phosphonic acid functionality of
FPMPs into a diamyl aspartate phenoxyamidate group resulted in a novel generation
of compounds having considerably improved antiretroviral potency as well as a larger
spectrum of antiviral activity including HBV and herpesviruses. The (S)-FPMPA amidate
prodrug displayed interesting activity against HIV (in the low nanomolar range), HBV and
VZV. The (S)-FPMPA amidate prodrug (compound 22a), one of the most active compounds,
had 2000-fold better activity than the parent phosphonate against both TK+ and TK−
VZV strains (EC50 s in the 0.05 µM range). Compound 22a was also active against HCMV
but lacked selectivity for HCMV (CC50 = 1.96 µM for HEL cells, which was lower than
the HCMV EC50 values) though it proved selective for VZV. Compounds 25a and 25b
(both enantiomers of the guanine containing amidate prodrugs) showed similar activity
and selectivity against VZV (EC50 ’s in the 0.079−0.89 µM range) and HCMV (EC50 ’s in
the 1.98−5.94 µM range), but compound 25b proved more active against HIV and HBV
than its diasteromer 25a. Among the pyrimidine analogues, compound 23a (the cytosine
containing (S)-Asp-prodrug) was the only congener displaying moderate activity against
both VZV TK+ (EC50 = 3.15 µM) and TK− (EC50 = 1.32 µM) viruses and against HCMV
[EC50 = 0.76 µM (AD-169 strain) and EC50 = 2.02 µM (Davis strain)].
7.1.11. Amidate Prodrugs of Cyclic 9-(S)-[3-Hydroxy-2-(phosphonomethoxy)

propyl]adenine, cHPMPA
The use of aryloxy monoamidates, a promising prodrug strategy for nucleoside
phosphates and phosphonates developed the last years, was applied to HPMP-based
compounds, resulting in the synthesis of phosphono amidate prodrugs of (S)-cHPMPA
bearing different amino acid motifs [116]. All (S)-cHPMPA phosphonamidates prodrugs
displayed broad-spectrum activity against herpesviruses with EC50 values in the low
nanomolar range. Compound 8a (cHPMPA diamyl aspartate phosphonoamidate prodrug)
(Table 3) displayed good activity against HSV, VZV, and HCMV (EC50 values in the
0.0009−0.027 µM range, being the EC50 ’s for VZV of ~0.0005 µM) while the (R)-counterpart
8b showed 24- to 180-fold lower potency. The (S)-Phe-cHPMPA (10), (S)-Glu-cHPMPA
(13), (S)-Val-cHPMPA (14), (S)-Leu-cHPMPA (15), and (S)-Ile-cHPMPA (16) had also very
potent anti-herpesvirus activity, with EC50 values of 0.00045−0.0043 µM for VZV. The
structures of compounds 8b, 10, 13, 14 and 15 are not shown here but were reported by Luo
and colleagues [116]. Among these prodrugs, compound 16 (Table 3) inhibited VZV with
EC50 ’s of 0.00045–0.00054 µM and emerged as the most selective one (selectivity indices’
of 20,000 and 1800, for VZV and HCMV, respectively). All prodrugs showed improved
antiviral properties compared to the parent compound, which can be explained by their
increased lipophilicity leading to enhanced cellular permeability. Additionally, HPMPA
Molecules 2021, 26, 1132 26 of 34
prodrugs displayed more potent activity than the reference anti-herpesvirus drugs and
were equally active against wild-type and TK− mutants of HSV and VZV. Furthermore,
the leucine ester prodrug of (S)-cHPMPA as well as the phosphonobisamidate valine ester
prodrug of (S)-HPMPA were shown to be stable in human plasma.
7.2. Non-Nucleoside Analogues

7.2.1. Pyrazolo[1,5-c]1,3,5-triazin-4-one Derivative
A derivative of pyrazolo[1,5-c]1,3,5-triazin-4-one, coded as 35B2 (2-[(2,6-dichlorophenyl)
methylthio]-3H-pyrazolo[1,5-c]1,3,5-triazin-4-one) (Table 3) was identified from a library of
9600 random compounds as a novel anti-VZV compound screened by using a reporter cell
line that produces luciferase upon infection with VZV [117]. The EC50 value for the vOka
strain was 0.75 µM and the selective index was more than 200. The compound inhibited
neither immediate-early gene expression nor viral DNA synthesis. Viral clones resistant to
35B2 had a mutation(s) in the amino acid sequence of the open reading frame 40 (ORF40),
which encodes the major capsid protein, with most of the mutations located in the regions
corresponding to the “floor” domain of the major capsid protein of HSV-1. Treatment with
35B2 altered the localization of major capsid protein in vOka-infected fibroblasts but not in
fibroblasts infected with the drug-resistant clones. Normal major capsid protein localization
in the 35B2-treated infected cells was restored by overexpression of the scaffold proteins.
Using electron microscopic analysis, lack of capsid formation could be demonstrated in
the 35B2-treated infected cells. These findings indicated a new class of anti-VZV agents
targeting the herpesvirus major capsid proteins and inhibiting normal capsid formation.
7.2.2. 5-Chlorobenzo[b]thiophen Derivative

From the screening of the 9600 compounds in the search of anti-VZV inhibitors,
the compound [(5-chlorobenzo[b]thiophen-3-yl)methyl][(4-chlorophenyl)sulfonyl]amine,
coded as 45B5 (Table 3), was identified also as a new anti-VZV agent [118]. Its EC50 against
VZV vOka in HEL was 16.9 µM and its CC50 was >100 µM. The EC50 values against the
parental Oka strain, acyclovir-resistant strains and 35B2-resistant strains were similar to
that against the vOka strain. Treatment of cells with 45B5 led to a weak but significant
decrease of viral DNA synthesis and IE62 expression. Several 45B5-resistant viral clones
were isolated and characterized, having all of them at least one mutation in the ORF54
that encodes the portal protein. No effects on interaction between the portal and scaffold
proteins were found, suggesting that 45B5 may inhibit nuclear delivery of viral DNA.
7.2.3. Thienylcarboxamide Derivative

The screening of 9600 compounds also allowed the identification of a thienylcar-
boxamide derivative, coded as 133G4 [N-(4-chlorophenyl)-5-nitro-3-thienylcarboxamide]
(Table 3), which was effective not only against VZV (EC50 = 19.3 µM) but also against
HCMV [119]. The compound displayed a selectivity of 27.8 and >35.5 µM against VZV and
HCMV, respectively. It was concluded that 133G4 was able to inhibit the activation of early
gene promoters by HCMV IE2 and VZV IE62 considering that: (i) in HCMV-infected cells,
133G4 reduced HCMV early and late genes expression but not HCMV immediately early
(IE1/IE2) gene expression, (ii) in HCMV-infected cells, 133G4 inhibited the activation of
various HCMV early gene promoters of transiently-transfected plasmids, and (iii) in tran-
sient transfection assays, the compound reduced activation of HCMV (or VZV) early gene
promoters by HCMV IE2 (or VZV IE62) in absence of other viral proteins. The inhibition of
early gene activation was cell dependent as it was demonstrated in human and African
green monkey cell lines but not in rodent cell lines, being the compound not effective
against murine CMV. It was then hypothesized that 133G4 may target a cellular factor used
commonly in activation of human herpesvirus promoters, however, the compound did
not inhibit the recruitment of some cellular proteins that have been well-characterized as
involved in VZV IE62-dependent viral gene activation to their binding sites, nor inhibited
the direct interactions of VZV IE62 with cellular proteins.
Molecules 2021, 26, 1132 27 of 34
7.2.4. Indole-Based Derivatives

A library of indole-based derivatives was designed, synthesized and evaluated for
antiviral activity against a broad spectrum of viruses [120]. The N-biphenylethyl acetamide
derivative 17a (Table 3) displayed significant inhibitory activity against VZV replication,
including TK+ and TK− VZV strains, pointing to a mechanism of action independent from
the virus-encoded thymidine kinase. Compound 17a inhibited VZV plaque formation with
EC50 ’s of 1.7–3.6 µM and a selectivity of 10–20 (ratio MCC/ EC50 ), being inactive against a
variety of RNA and DNA viruses. A structure-activity relationship study showed that the
substitution on the tryptamine moiety strongly influenced the compounds’ activity/toxicity.
The concomitant presence of a biphenyl and methyl(phenyl) carboxy group at the amino
group of tryptamine was required for anti-VZV activity.
7.2.5. Cephalotaxine Esters

The alkaloid esters isolated from the genus Cephalotaxus, harringtonine (HT) and
homoharringtonine (HHT) (Table 3), exhibit antitumor activity. Indeed, a semisynthetic
HHT, omacetaxine mepesuccinate, has been approved by the FDA for treatment of chronic
myelogenous leukemia patients resistant or intolerant to tyrosine kinase inhibitors. In
addition to their known antitumor activity, HT and HHT possess potent antiviral activity
with HT inhibiting chikungunya virus replication through down-regulation of viral protein
expression and HHT displaying activity against HBV and coronavirus. HT and HHT, but
not their biologically inactive parental alkaloid cephalotaxine, significantly hampered VZV
replication of the recombinant VZV-pOka luciferase strain and a clinical isolate of VZV
in vitro though the anti-VZV activity was lower for the clinical isolate than the reference
strain [121]. HT and HHT reduced plaque formation with an estimated EC50 of 16.15 and
9.96 ng/mL, respectively. Their selectivity indices were low considering their CC50 values,
i.e., 45.82 ng/mL (HT) and 74.71 ng/mL (HTT). The inhibition of VZV replication by HT
and HHT was related to down-regulation of VZV lytic genes.
Given that HT and HHT inhibit replication of both RNA and DNA viruses, antiviral
activities could be due to effects on cellular rather than viral factor(s) required for viral
replication. HT and HHT were suggested to interfere with signal transduction pathways
and transcription factors involved in VZV lytic gene expression. Furthermore, HT and
HHT were reported to block cell cycle progression at G1/S or G2/M transition and consid-
ering that cell cycle regulation affects herpesvirus lytic gene expression and replication,
a plausible mechanism to explain the anti-VZV activity of HT and HHT may be through
effects on cell cycle in infected cells [120]. This study supports the potential of HT and
HHT as candidates for treatment of VZV-associated diseases.
7.3. Hybrid Molecules

Dihydropyrimidinone/1,2,3-triazole Hybrid Molecules
A feasible strategy for producing drug molecules with potent activity is to combine
two bioactive molecules belonging to different therapeutic categories. For instance, 1,2,3-
triazole-based heterocycles have been used for the generation of many medicinal scaffolds
with inhibitory properties against several viruses, including VZV. The multi-functionalized
pyrimidinone scaffold represents a class of heterocyclic compounds with known pharma-
cological efficiency, including antiviral activity. Therefore, the synthesis of novel hybrid
molecules can be regarded as a way to increase activity and/or decreased toxicity of the
molecules. Novel hybrid compounds have been synthesized by combining the structural
features of dihydropyrimidinone and 1,2,3-triazole heterocycles. Some of the tested com-
pounds showed valuable antiviral activities, with EC50 values ranging from 3.6 to 11.3 µM
against TK+ and TK− VZV and without measurable cell-growth inhibition. Compound
8a (Table 3) emerged as the most active derivative with antiviral activities against VZV
at EC50 of 3.62 µM (TK+ strain) and 7.85 µM (TK− strain) and CC50 >100 µM, followed
by compound 7d [EC50 of ~10–11 µM and CC50 >100 µM] [122]. None of the tested com-
pounds exhibited measurable antiviral activity against HCMV. These findings suggest a
Molecules 2021, 26, 1132 28 of 34
selectivity of dihydropyrimidinone/1,2,3-triazole hybrid molecules into the herpesviridae

family against VZV.
8. Conclusions and Perspectives

Despite the availability of a vaccine for the prevention of pediatric varicella in children
and for the prevention of HZ in adults, there will continue to be a need for antiviral
drugs. Some people in the elderly category are not able to mount a strong response to the
vaccine. In immunocompromised persons, including patients with advanced HIV infection,
varicella vaccination should be done exclusively with the subunit HZ vaccine as the life-
attenuated vaccine is contraindicated for fear of disseminated vaccine-induced disease. On
the other hand, the vaccine coverage is still quite limited and childhood immunization
with lower coverage could theoretically shift the epidemiology of the disease leading to an
increase in the number of severe cases in older children, teenagers and adults.
Infections with VZV are a serious cause of morbidity and mortality among immuno-
suppressed patients and in the elderly as PHN (the major complication of HZ) can be very
difficult to manage. Currently available antiviral agents can shorten the duration of HZ
and can promote rash healing, though they are not quite effective in preventing PHN,
most likely due to the delay between diagnosis and the start of antiviral treatment. New
antiviral chemotherapeutics with a different mechanism of action are under development
for the management of HZ, including valnivudine hydrochloride (FV-100), prodrug of the
bicyclic nucleoside analogue Cf-1743, the helicase-primase inhibitor amenamevir (ASP2151)
that got only approval in Japan because of toxicity issues, and the carbocyclic nucleoside
analogue valomaciclovir stearate (EPB-348), the omaciclovir prodrug. Although the de-
velopment of amenamevir has been halted due to problems of toxicity following a trial
in United States, the results with valnivudine hydrochloride and valomaciclovir stearate
indicated that these drugs are effective, well-tolerated, with once-daily therapy regimen
in the treatment of HZ. Further studies are needed to prove an advantage of valnivudine
hydrochloride (FV-100) and valomaciclovir stearate over the standard of care valacyclovir.
The development of other helicase-primase inhibitors and new drugs with a different target
against VZV would be of value to manage ACV-resistant strains. Furthermore, inhibition of
multiple targets in the viral replication cycle has the potential for synergistic effects when
used in combination therapy, which would be of particular importance for immunocompro-
mised hosts because it may avoid the need for extended therapeutic regimens and the risk
of developing antiviral resistance during prolonged monotherapy. A potential anti-VZV
drug candidate needs to be at least as effective and safe as the gold standard of treatment
for HZ, i.e., valacyclovir. It will need to have also some advantages over valacyclovir, such
as longer intracellular half-life allowing once a day dosing, superior efficacy, independence
of TK for activation and/or target another enzyme than the DNA polymerase.
Antiviral agents will still have a role in the treatment of VZV-associated diseases. A
large percentage of the HZ at-risk population does not receive the vaccine. The currently
FDA-approved antiviral drugs, including acyclovir, valacyclovir and famciclovir have low
efficacy in the control of pain for HZ patients and a significant proportion of these patients
(~20–40%) develops PHN. These antivirals require multiple dosing regimens daily that
need to be modified for patients with renal failure. Treatment with currently approved
antiviral agents is recommended for VZV-associated infections in immunocompromised
individuals, where VZV infections can be very severe. Among immunocompetent patients,
antiviral therapy is recommended for adolescents and adults suffering from varicella and
for patients (especially those older than 50 years) with HZ. Antiviral therapy will also be
valuable to treat rare but significant side effects caused by the VZV vaccine. Although
development of drug-resistance in considered much less common in VZV than in HSV,
emergence of VZV drug-resistance in an emerging concern among immunosuppressed
patients who have received prolonged antiviral therapy. Novel antiviral chemotherapeutics
with different mode of action than the currently available anti-VZV drugs are required
for the treatment of ACV-resistant strains in the immunocompromised host. Furthermore,
Molecules 2021, 26, 1132 29 of 34
compounds with a better activity than the currently approved drugs will be extremely
useful if they are able to shorten the time to complete crusting of the shingles rash, time to
complete pain resolution and prevention of PHN.
In the medical literature, cases of coronavirus disease 2019 (COVID-19) and HZ co-
infections are being reported. An atypical bilateral acute retinal necrosis was diagnosed
in a COVID-19 positive 75-year-old woman, who was immunosuppressed because of
chemotherapy for a relapse of diffuse large cell B-cell lymphoma (DLBCL) [123]. Tartari
and colleagues reported four cases of HZ in COVID-19 patients over 65 years old, three of
them being admitted to ICU, requiring mechanical ventilation, and developing a necrotic
HZ on the second branch of the trigeminal nerve [124]. The fourth patient, under immune
suppressive therapy because of a cardiac transplant, showed a more indolent COVID-19
disease not requiring hospitalization and developed a classical HZ. Shors reported on
a 49-year-old who developed HZ lesions 7 days following the emergence of COVID-19
symptoms and despite receiving valacyclovir 1 g 3× daily within 12 h of the initial eruption,
the patient developed severe herpetic neuralgia [125]. A case of an immunocompetent
middle-aged man presented with COVID-19 and 2 days later developed HZ. In another
report, two cases of HZ reactivation preceding the emergence of respiratory symptoms in
COVID-19 patients were demonstrated [126]. Furthermore, HZ may occur in asymptomatic
COVID-19 patients, as found in a 39-year-old immunocompetent man who proved COVID-
19 positive but symptoms free and presented HZ with trigeminal neuropathy [127]. These
studies suggest an association between COVID-19 and VZV reactivation [128]. Given the
nature of VZV reactivation, most commonly linked to stress, advanced age, and impaired
immune conditions, more co-infection cases are expected to follow, which will require
not only management of COVID-19 but also of VZV disease. To date VZV reactivation
in COVID-19 patients has been described mostly in immunocompetent individuals and
it has been proposed that the acute COVID-19 disease, associated with physical and
emotional stress, might be a trigger factor for the development of HZ. Covid-19-associated
lymphopenia, occurring due to direct damage to the thymus and spleen or due to the
induced cytokine storm may impair antiviral responses. Furthermore, corticosteroids are
being used to manage COVID-19, which may also favor VZV reactivation. Therefore,
reactivation of herpesviruses, in particular of VZV, could be an emerging complication
of COVID-19. Considering the ongoing COVID-19 pandemic, the CDC recommends
vaccination against shingles for individuals at high risk, in particular for patients ≥50 years
old. Besides, more potent and selective anti-VZV agents would be important to treat the
unusual presentations and complications of HZ in COVID-19 patients.
Author Contributions: Conceptualization, G.A.; writing—original draft preparation, G.A.; writing—

review and editing, G.A. and R.S. All authors have read and agreed to the published version of the
manuscript.
Funding: This research received no external funding.
Conflicts of Interest: The authors declare no conflict of interest
References
1. Breuer, J.; Whitley, R. Varicella zoster virus: Natural history and current therapies of varicella and herpes zoster. Herpes 2007, 14,
25–29.
2. Gershon, A.A.; Gershon, M.D.; Breuer, J.; Levin, M.J.; Oaklander, A.L.; Griffiths, P.D. Advances in the understanding of the
pathogenesis and epidemiology of herpes zoster. J. Clin. Virol. 2010, 48, S2–S7. [CrossRef]
3. Defaux, B.A.; Brabant, S.; Chatellier, D.; Bourgoin, A.; Robert, R.; Ruckes, T.; Agius, G. Disseminated varicella with multiorgan
failure in an immunocompetent adult. J. Med. Virol. 2009, 81, 747–749. [CrossRef] [PubMed]
4. Scotch, A.H.; Hoss, E.; Orenstein, R.; Budavari, A.I. Disseminated Varicella-Zoster Virus After Vaccination in an Immunocompetent
Patient. J. Am. Osteopath. Assoc. 2016, 116, 402–405. [CrossRef] [PubMed]
5. Petrun, B.; Williams, V.; Brice, S. Disseminated varicella-zoster virus in an immunocompetent adult. Dermatol. Online J. 2015, 21.
[CrossRef]
6. Loftus, M.J.; Yong, M.K.; Wilson, S.; Peleg, A.Y. Fatal disseminated visceral varicella zoster virus infection in a renal transplant
recipient. Transpl. Infect. Dis. 2019, 21, 3062. [CrossRef] [PubMed]
Molecules 2021, 26, 1132 30 of 34
7. Lewis, D.J.; Schlichte, M.J.; Dao, H., Jr. Atypical disseminated herpes zoster: Management guidelines in immunocompromised
patients. Cutis 2017, 100, 321–330.
8. Johnson, R.W.; McElhaney, J. Postherpetic neuralgia in the elderly. Int. J. Clin. Pract. 2009, 63, 1386–1391. [CrossRef] [PubMed]
9. Opstelten, W.; McElhaney, J.; Weinberger, B.; Oaklander, A.L.; Johnson, R.W. The impact of varicella zoster virus: Chronic pain. J.
Clin. Virol. 2010, 48, S8–S13. [CrossRef]
10. McElhaney, J.E. Herpes zoster: A common disease that can have a devastating impact on patients’ quality of life. Expert Rev.
Vaccines 2010, 9, 27–30. [CrossRef]
11. Davis, A.R.; Sheppard, J. Herpes Zoster Ophthalmicus Review and Prevention. Eye Contact Lens. 2019, 45, 286–291. [CrossRef]
12. Kedar, S.; Jayagopal, L.N.; Berger, J.R. Neurological and Ophthalmological Manifestations of Varicella Zoster Virus. J. Neurooph-
thalmol. 2019, 39, 220–231. [CrossRef]
13. Depledge, D.P.; Cudini, J.; Kundu, S.; Atkinson, C.; Brown, J.R.; Haque, T.; Houldcroft, C.J.; Koay, E.S.; McGill, F.; Milne, R.; et al.
High Viral Diversity and Mixed Infections in Cerebral Spinal Fluid from Cases of Varicella Zoster Virus Encephalitis. J. Infect. Dis.
2018, 218, 1592–1601. [CrossRef]
14. Wauters, O.; Lebas, E.; Nikkels, A.F. Chronic mucocutaneous herpes simplex virus and varicella zoster virus infections. J. Am.
Acad. Dermatol. 2012, 66, e217–e227. [CrossRef]
15. Johnson, R.W.; Pasquin, A.M.J.; Bijl, M.; Franco, E.; Gaillat, J.; Clara, J.G.; Labetoulle, M.; Michel, J.P.; Naldi, L.; Sanmarti, L.S.;
et al. Herpes zoster epidemiology, management, and disease and economic burden in Europe: A multidisciplinary perspective.
Ther. Adv. Vaccines 2015, 3, 109–120. [CrossRef] [PubMed]
16. Mueller, N.H.; Gilden, D.H.; Cohrs, R.J.; Mahalingam, R.; Nagel, M.A. Varicella zoster virus infection: Clinical features, molecular
pathogenesis of disease, and latency. Neurol. Clin. 2008, 26, 675–697. [CrossRef]
17. Bergstrom, R.; Tripathy, K. Acute Retinal Necrosis; StatPearls: Treasure Island, FL, USA, 2019.
18. Pavesio, C.E.; Mitchell, S.M.; Barton, K.; Schwartz, S.D.; Towler, H.M.; Lightman, S. Progressive outer retinal necrosis (PORN) in
AIDS patients: A different appearance of varicella-zoster retinitis. Eye 1995, 9, 271–276. [CrossRef]
19. Yin, P.D.; Kurup, S.K.; Fischer, S.H.; Rhee, H.H.; Byrnes, G.A.; Clarke, L.G.A.; Buggage, R.R.; Nussenblatt, R.B.; Mican, J.M.;
Wright, M.E. Progressive outer retinal necrosis in the era of highly active antiretroviral therapy: Successful management with
intravitreal injections and monitoring with quantitative PCR. J. Clin. Virol. 2007, 38, 254–259. [CrossRef]
20. Austin, R.B. Progressive outer retinal necrosis syndrome: A comprehensive review of its clinical presentation, relationship to
immune system status, and management. Clin. Eye Vis. Care 2000, 12, 119–129. [CrossRef]
21. Gunturu, M.; Gosi, S.K.; Kanduri, S.; Garla, V. Varicella Zoster Meningitis, Optic Neuritis Preceding the Development of Posterior
Outer Retinal Necrosis, and Central Retinal Artery Occlusion in a HIV Patient. Case Rep. Med. 2019, 2019, 3162. [CrossRef]
22. Baxter, R.; Ray, P.; Tran, T.N.; Black, S.; Shinefield, H.R.; Coplan, P.M.; Lewis, E.; Fireman, B.; Saddier, P. Long-term effectiveness
of varicella vaccine: A 14-Year, prospective cohort study. Pediatrics 2013, 131, e1389–e1396. [CrossRef] [PubMed]
23. Marin, M.; Leung, J.; Gershon, A.A. Transmission of Vaccine-Strain Varicella-Zoster Virus: A Systematic Review. Pediatrics 2019,
144. [CrossRef]
24. Norberg, P.; Depledge, D.P.; Kundu, S.; Atkinson, C.; Brown, J.; Haque, T.; Hussaini, Y.; MacMahon, E.; Molyneaux, P.;
Papaevangelou, V.; et al. Recombination of Globally Circulating Varicella-Zoster Virus. J. Virol. 2015, 89, 7133–7146. [CrossRef]
25. Bastidas, A.; de la Serna, J.; El Idrissi, M.; Oostvogels, L.; Quittet, P.; Jimenez, L.J.; Vural, F.; Pohlreich, D.; Zuckerman, T.; Issa,
N.C.; et al. Effect of Recombinant Zoster Vaccine on Incidence of Herpes Zoster After Autologous Stem Cell Transplantation: A
Randomized Clinical Trial. JAMA 2019, 322, 123–133. [CrossRef] [PubMed]
26. Perry, C.M.; Faulds, D. Valaciclovir. A review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy in
herpesvirus infections. Drugs 1996, 52, 754–772. [CrossRef]
27. Perry, C.M.; Wagstaff, A.J. Famciclovir. A review of its pharmacological properties and therapeutic efficacy in herpesvirus
infections. Drugs 1995, 50, 396–415. [CrossRef] [PubMed]
28. Hodge, V.R.A.; Sutton, D.; Boyd, M.R.; Harnden, M.R.; Jarvest, R.L. Selection of an oral prodrug (BRL 42810; famciclovir) for the
antiherpesvirus agent BRL 39123 (9-(4-hydroxy-3-hydroxymethylbut-l-yl)guanine; penciclovir). Antimicrob. Agents Chemother.
1989, 33, 1765–1773. [CrossRef] [PubMed]
29. De Clercq, E. Discovery and development of BVDU (brivudin) as a therapeutic for the treatment of herpes zoster. Biochem.
Pharmacol. 2004, 68, 2301–2315. [CrossRef]
30. Wutzler, P. Antiviral therapy of herpes simplex and varicella-zoster virus infections. Intervirology 1997, 40, 343–356. [CrossRef]
31. Yaldiz, M.; Solak, B.; Kara, R.O.; Cosansu, N.; Erdem, M.T. Comparison of Famciclovir, Valaciclovir, and Brivudine Treatments in
Adult Immunocompetent Patients with Herpes Zoster. Am. J. Ther. 2018, 25, e626–e634. [CrossRef]
32. Desgranges, C.; Razaka, G.; De Clercq, E.; Herdewijn, P.; Balzarini, J.; Drouillet, F.; Bricaud, H. Effect of (E)-5-(2-bromovinyl)uracil
on the catabolism and antitumor activity of 5-fluorouracil in rats and leukemic mice. Cancer Res. 1986, 46, 1094–1101.
33. Tsifi, A.; Papaxoinis, G.; Diamantopoulos, P.; Mantzourani, M.; Antoniadou, V.; Halioti, A.; Gogas, H. A life-threatening drug-
drug interaction between capecitabine and brivudine in a patient with metastatic breast cancer. J. Chemother. 2019, 31, 424–427.
[CrossRef]
34. Canada, B.J.M.; Martinez, M.J.; Olmedo, G.O.; Barcenas, J.R.; Cueto, M.P. Interaction between capecitabine and brivudin in a
patient with breast cancer. Nat. Rev. Clin. Oncol. 2010, 7, 55–58. [CrossRef]
Molecules 2021, 26, 1132 31 of 34
35. Bravo, R.A.E.; Hofer, S.; Krahenbuhl, S.; Ludwig, C. Fatal drug-drug interaction of brivudine and capecitabine. Acta Oncol. 2009,
48, 631–633. [CrossRef] [PubMed]
36. Okuda, H.; Ogura, K.; Kato, A.; Takubo, H.; Watabe, T. A possible mechanism of eighteen patient deaths caused by interactions of
sorivudine, a new antiviral drug, with oral 5-fluorouracil prodrugs. J. Pharmacol. Exp. Ther. 1998, 287, 791–799.
37. Okuda, H.; Nishiyama, T.; Ogura, K.; Nagayama, S.; Ikeda, K.; Yamaguchi, S.; Nakamura, Y.; Kawaguchi, K.; Watabe, T.; Ogura, Y.
Lethal drug interactions of sorivudine, a new antiviral drug, with oral 5-fluorouracil prodrugs. Drug Metab. Dispos. 1997, 25,
270–273. [PubMed]
38. Chono, K.; Katsumata, K.; Kontani, T.; Kobayashi, M.; Sudo, K.; Yokota, T.; Konno, K.; Shimizu, Y.; Suzuki, H. ASP2151, a novel
helicase-primase inhibitor, possesses antiviral activity against varicella-zoster virus and herpes simplex virus types 1 and 2. J.
Antimicrob. Chemother. 2010, 65, 1733–1741. [CrossRef]
39. Kleymann, G. New antiviral drugs that target herpesvirus helicase primase enzymes. Herpes 2003, 10, 46–52.
40. Chono, K.; Katsumata, K.; Suzuki, H.; Shiraki, K. Synergistic activity of amenamevir (ASP2151) with nucleoside analogs against
herpes simplex virus types 1 and 2 and varicella-zoster virus. Antivir. Res. 2012, 97, 154–160. [CrossRef]
41. Chono, K.; Katsumata, K.; Kontani, T.; Shiraki, K.; Suzuki, H. Characterization of virus strains resistant to the herpes virus
helicase-primase inhibitor ASP2151 (Amenamevir). Biochem. Pharmacol. 2012, 84, 459–467. [CrossRef] [PubMed]
42. Birkmann, A.; Zimmermann, H. Drugs in development for herpes simplex and varicella zoster virus. Clin. Pharmacol. Ther. 2017,
43. Kawashima, M.; Nemoto, O.; Honda, M.; Watanabe, D.; Nakayama, J.; Imafuku, S.; Kato, T.; Katsuramaki, T.; Study, I. Amenamevir,
a novel helicase-primase inhibitor, for treatment of herpes zoster: A randomized, double-blind, valaciclovir-controlled phase 3
study. J. Dermatol. 2017, 44, 1219–1227. [CrossRef]
44. Whitley, R.J.; Volpi, A.; McKendrick, M.; Wijck, A.; Oaklander, A.L. Management of herpes zoster and post-herpetic neuralgia
now and in the future. J. Clin. Virol. 2010, 48, S20–S28. [CrossRef]
45. Levy, O.; Orange, J.S.; Hibberd, P.; Steinberg, S.; La Russa, P.; Weinberg, A.; Wilson, S.B.; Shaulov, A.; Fleisher, G.; Geha, R.S.; et al.
Disseminated varicella infection due to the vaccine strain of varicella-zoster virus, in a patient with a novel deficiency in natural
killer T cells. J. Infect. Dis. 2003, 188, 948–953. [CrossRef]
46. Galea, S.A.; Sweet, A.; Beninger, P.; Steinberg, S.P.; Larussa, P.S.; Gershon, A.A.; Sharrar, R.G. The safety profile of varicella
vaccine: A 10-year review. J. Infect. Dis. 2008, 197, S165–S169. [CrossRef] [PubMed]
47. Ota, K.; Kim, V.; Lavi, S.; Jones, F.E.L.; Tipples, G.; Scolnik, D.; Tellier, R. Vaccine-strain varicella zoster virus causing recurrent
herpes zoster in an immunocompetent 2-year-old. Pediatr. Infect. Dis. J. 2008, 27, 847–848. [CrossRef] [PubMed]
48. Uebe, B.; Sauerbrei, A.; Burdach, S.; Horneff, G. Herpes zoster by reactivated vaccine varicella zoster virus in a healthy child. Eur.
J. Pediatr. 2002, 161, 442–444. [CrossRef] [PubMed]
49. Tseng, H.F.; Schmid, D.S.; Harpaz, R.; La Russa, P.; Jensen, N.J.; Rivailler, P.; Radford, K.; Folster, J.; Jacobsen, S.J. Herpes zoster
caused by vaccine-strain varicella zoster virus in an immunocompetent recipient of zoster vaccine. Clin. Infect. Dis. 2014, 58,
1125–1128. [CrossRef] [PubMed]
50. Fusco, D.; Krawitz, P.; La Russa, P.; Steinberg, S.; Gershon, A.; Jacobs, J. VZV meningitis following varicella vaccine. J. Clin. Virol.
2010, 48, 275–277. [CrossRef] [PubMed]
51. Han, J.Y.; Hanson, D.C.; Way, S.S. Herpes zoster and meningitis due to reactivation of varicella vaccine virus in an immunocom-
petent child. Pediatr. Infect. Dis. J. 2011, 30, 266–268. [CrossRef]
52. Chouliaras, G.; Spoulou, V.; Quinlivan, M.; Breuer, J.; Theodoridou, M. Vaccine-associated herpes zoster ophthalmicus [correction
of opthalmicus] and encephalitis in an immunocompetent child. Pediatrics 2010, 125, e969–e972. [CrossRef] [PubMed]
53. Davidson, N.; Broom, J. Vaccine strain varicella zoster virus transmitted within a family from a child with shingles results in
varicella meningitis in an immunocompetent adult. Intern. Med. J. 2019, 49, 132–133. [CrossRef] [PubMed]
54. Pahwa, S.; Biron, K.; Lim, W.; Swenson, P.; Kaplan, M.H.; Sadick, N.; Pahwa, R. Continuous varicella-zoster infection associated
with acyclovir resistance in a child with AIDS. JAMA 1988, 260, 2879–2882. [CrossRef]
55. Snoeck, R.; Gerard, M.; Delvaux, S.C.; Andrei, G.; Balzarini, J.; Reymen, D.; Ahadi, N.; De Bruyn, J.M.; Piette, J.; Rentier, B.; et al.
Meningoradiculoneuritis due to acyclovir-resistant varicella zoster virus in an acquired immune deficiency syndrome patient. J.
Med. Virol. 1994, 42, 338–347. [CrossRef] [PubMed]
56. Boivin, G.; Edelman, C.K.; Pedneault, L.; Talarico, C.L.; Biron, K.K.; Balfour, H.H., Jr. Phenotypic and genotypic characterization of
acyclovir-resistant varicella-zoster viruses isolated from persons with AIDS. J. Infect. Dis. 1994, 170, 68–75. [CrossRef] [PubMed]
57. Talarico, C.L.; Phelps, W.C.; Biron, K.K. Analysis of the thymidine kinase genes from acyclovir-resistant mutants of varicella-zoster
virus isolated from patients with AIDS. J. Virol. 1993, 67, 1024–1033. [CrossRef] [PubMed]
58. Piret, J.; Boivin, G. Antiviral resistance in herpes simplex virus and varicella-zoster virus infections: Diagnosis and management.
Curr. Opin. Infect. Dis. 2016, 29, 654–662. [CrossRef] [PubMed]
59. van der Beek, M.T.; Vermont, C.L.; Bredius, R.G.; Marijt, E.W.; van der Blij-de Brouwer, C.S.; Kroes, A.C.; Claas, E.C.; Vossen,
A.C. Persistence and Antiviral Resistance of Varicella Zoster Virus in Hematological Patients. Clin. Infect. Dis. 2012, 56, 335–343.
[CrossRef]
60. Brink, A.A.; van Gelder, M.; Wolffs, P.F.; Bruggeman, C.A.; van Loo, I.H. Compartmentalization of acyclovir-resistant varicella
zoster virus: Implications for sampling in molecular diagnostics. Clin. Infect. Dis. 2011, 52, 982–987. [CrossRef]
Molecules 2021, 26, 1132 32 of 34
61. Gueudry, J.; Boutolleau, D.; Gueudin, M.; Burrel, S.; Miri, A.; Bodaghi, B.; Muraine, M. Acyclovir-resistant varicella-zoster virus
keratitis in an immunocompetent patient. J. Clin. Virol. 2013, 58, 318–320. [CrossRef]
62. Gilbert, C.; Smith, B.J.; Boivin, G. Resistance of herpesviruses to antiviral drugs: Clinical impacts and molecular mechanisms.
Drug Resist. Updates 2002, 5, 88–114. [CrossRef]
63. Andrei, G.; Topalis, D.; Fiten, P.; McGuigan, C.; Balzarini, J.; Opdenakker, G.; Snoeck, R. In vitro-selected drug-resistant varicella-
zoster virus mutants in the thymidine kinase and DNA polymerase genes yield novel phenotype-genotype associations and
highlight differences between antiherpesvirus drugs. J. Virol. 2012, 86, 2641–2652. [CrossRef] [PubMed]
64. Topalis, D.; Gillemot, S.; Snoeck, R.; Andrei, G. Thymidine kinase and protein kinase in drug-resistant herpesviruses: Heads of a
Lernaean Hydra. Drug Resist. Updates 2018, 37, 1–16. [CrossRef] [PubMed]
65. Morfin, F.; Thouvenot, D.; Tessier, T.M.; Lina, B.; Aymard, M.; Ooka, T. Phenotypic and genetic characterization of thymidine
kinase from clinical strains of varicella-zoster virus resistant to acyclovir. Antimicrob. Agents Chemother. 1999, 43, 2412–2416.
[CrossRef]
66. Piret, J.; Boivin, G. Antiviral drug resistance in herpesviruses other than cytomegalovirus. Rev. Med. Virol. 2014, 24, 186–218.
[CrossRef]
67. Hatchette, T.; Tipples, G.A.; Peters, G.; Alsuwaidi, A.; Zhou, J.; Mailman, T.L. Foscarnet salvage therapy for acyclovir-resistant
varicella zoster: Report of a novel thymidine kinase mutation and review of the literature. Pediatr. Infect. Dis. J. 2008, 27, 75–77.
[CrossRef]
68. Safrin, S.; Berger, T.G.; Gilson, I.; Wolfe, P.R.; Wofsy, C.B.; Mills, J.; Biron, K.K. Foscarnet therapy in five patients with AIDS and
acyclovir-resistant varicella-zoster virus infection. Ann. Intern. Med. 1991, 115, 19–21. [CrossRef] [PubMed]
69. Bryan, C.J.; Prichard, M.N.; Daily, S.; Jefferson, G.; Hartline, C.; Cassady, K.A.; Hilliard, L.; Shimamura, M. Acyclovir-resistant
chronic verrucous vaccine strain varicella in a patient with neuroblastoma. Pediatr. Infect. Dis. J. 2008, 27, 946–948. [CrossRef]
70. Visse, B.; Dumont, B.; Huraux, J.M.; Fillet, A.M. Single amino acid change in DNA polymerase is associated with foscarnet
resistance in a varicella-zoster virus strain recovered from a patient with AIDS. J. Infect. Dis. 1998, 178, S55–S57. [CrossRef]
[PubMed]
71. Fillet, A.M.; Visse, B.; Caumes, E.; Dumont, B.; Gentilini, M.; Huraux, J.M. Foscarnet-resistant multidermatomal zoster in a patient
with AIDS. Clin. Infect. Dis. 1995, 21, 1348–1349. [CrossRef]
72. Visse, B.; Huraux, J.M.; Fillet, A.M. Point mutations in the varicella-zoster virus DNA polymerase gene confers resistance to
foscarnet and slow growth phenotype. J. Med. Virol. 1999, 59, 84–90. [CrossRef]
73. Andrei, G.; De Clercq, E.; Snoeck, R. In vitro selection of drug-resistant varicella-zoster virus (VZV) mutants (OKA strain):
Differences between acyclovir and penciclovir? Antivir. Res. 2004, 61, 181–187. [CrossRef] [PubMed]
74. Boyd, M.R.; Bacon, T.H.; Sutton, D.; Cole, M. Antiherpesvirus activity of 9-(4-hydroxy-3-hydroxy-methylbut-1-yl)guanine (BRL
39123) in cell culture. Antimicrob. Agents Chemother. 1987, 31, 1238–1242. [CrossRef]
75. Pelosi, E.; Mulamba, G.B.; Coen, D.M. Penciclovir and pathogenesis phenotypes of drug-resistant Herpes simplex virus mutants.
Antivir. Res. 1998, 37, 17–28. [CrossRef]
76. Hasegawa, T.; Kurokawa, M.; Yukawa, T.A.; Horii, M.; Shiraki, K. Inhibitory action of acyclovir (ACV) and penciclovir (PCV)
on plaque formation and partial cross-resistance of ACV-resistant varicella-zoster virus to PCV. Antivir. Res. 1995, 27, 271–279.
[CrossRef]
77. Ida, M.; Kageyama, S.; Sato, H.; Kamiyama, T.; Yamamura, J.; Kurokawa, M.; Morohashi, M.; Shiraki, K. Emergence of resistance
to acyclovir and penciclovir in varicella-zoster virus and genetic analysis of acyclovir-resistant variants. Antivir. Res. 1999, 40,
155–166. [CrossRef]
78. Stryjewski, T.P.; Scott, N.L.; Barshak, M.B.; Tobin, E.H.; Mali, J.O.; Young, L.H.; Foster, C.S.; Kim, I.K.; Durand, M.L. Treatment of
Refractory Acute Retinal Necrosis with Intravenous Foscarnet or Cidofovir. Ocul. Immunol. Inflamm. 2018, 26, 199–203. [CrossRef]
[PubMed]
79. Poole, C.L.; James, S.H. Antiviral Therapies for Herpesviruses: Current Agents and New Directions. Clin. Ther. 2018, 40,
1282–1298. [CrossRef]
80. Levin, M.J.; Dahl, K.M.; Weinberg, A.; Giller, R.; Patel, A.; Krause, P.R. Development of resistance to acyclovir during chronic
infection with the Oka vaccine strain of varicella-zoster virus, in an immunosuppressed child. J. Infect. Dis. 2003, 188, 954–959.
[CrossRef] [PubMed]
81. McGuigan, C.; Yarnold, C.J.; Jones, G.; Velazquez, S.; Barucki, H.; Brancale, A.; Andrei, G.; Snoeck, R.; De Clercq, E.; Balzarini, J.
Potent and selective inhibition of varicella-zoster virus (VZV) by nucleoside analogues with an unusual bicyclic base. J. Med.
Chem. 1999, 42, 4479–4484. [CrossRef] [PubMed]
82. McGuigan, C.; Barucki, H.; Carangio, A.; Blewett, S.; Andrei, G.; Snoeck, R.; De Clercq, E.; Balzarini, J.; Erichsen, J.T. Highly
potent and selective inhibition of varicella-zoster virus by bicyclic furopyrimidine nucleosides bearing an aryl side chain. J. Med.
Chem. 2000, 43, 4993–4997. [CrossRef]
83. Andrei, G.; Sienaert, R.; McGuigan, C.; De Clercq, E.; Balzarini, J.; Snoeck, R. Susceptibilities of several clinical Varicella-zoster
virus (VZV) isolates and drug-resistant VZV strains to bicyclic furano pyrimidine nucleosides. Antimicrob. Agents Chemother.
2005, 49, 1081–1086. [CrossRef] [PubMed]
84. Balzarini, J.; McGuigan, C. Chemotherapy of varicella-zoster virus by a novel class of highly specific anti-VZV bicyclic pyrimidine
nucleosides. Biochim. Biophys. Acta 2002, 1587, 287–295. [CrossRef]
Molecules 2021, 26, 1132 33 of 34
85. McGuigan, C.; Pathirana, R.N.; Migliore, M.; Adak, R.; Luoni, G.; Jones, A.T.; Torrubia, D.A.; Camarasa, M.J.; Velazquez, S.;
Henson, G.; et al. Preclinical development of bicyclic nucleoside analogues as potent and selective inhibitors of varicella zoster
virus. J. Antimicrob. Chemother. 2007, 60, 1316–1330. [CrossRef] [PubMed]
86. Sienaert, R.; Naesens, L.; Brancale, A.; Carangio, A.; Andrei, G.; Snoeck, R.; Van Kuilenburg, A.; De Clercq, E.; McGuigan, C.;
Balzarini, J. Metabolic and pharmacological characteristics of the bicyclic nucleoside analogues (BCNAs) as highly selective
inhibitors of varicella-zoster virus (VZV). Nucleosides Nucleotides Nucleic Acids 2003, 22, 995–997. [CrossRef]
87. Balzarini, J.; Sienaert, R.; Liekens, S.; Van Kuilenburg, A.; Carangio, A.; Esnouf, R.; De Clercq, E.; McGuigan, C. Lack of
susceptibility of bicyclic nucleoside analogs, highly potent inhibitors of varicella-zoster virus, to the catabolic action of thymidine
phosphorylase and dihydropyrimidine dehydrogenase. Mol. Pharmacol. 2002, 61, 1140–1145. [CrossRef] [PubMed]
88. Sienaert, R.; Naesens, L.; Brancale, A.; De Clercq, E.; McGuigan, C.; Balzarini, J. Specific recognition of the bicyclic pyrimidine
nucleoside analogs, a new class of highly potent and selective inhibitors of varicella-zoster virus (VZV), by the VZV-encoded
thymidine kinase. Mol. Pharmacol. 2002, 61, 249–254. [CrossRef] [PubMed]
89. Pentikis, H.S.; Matson, M.; Atiee, G.; Boehlecke, B.; Hutchins, J.T.; Patti, J.M.; Henson, G.W.; Morris, A. Pharmacokinetics and
safety of FV-100, a novel oral anti-herpes zoster nucleoside analogue, administered in single and multiple doses to healthy young
adult and elderly adult volunteers. Antimicrob. Agents Chemother. 2011, 55, 2847–2854. [CrossRef]
90. Tyring, S.K.; Lee, P.; Hill, G.T., Jr.; Silverfield, J.C.; Moore, A.Y.; Matkovits, T.; Bolyai, S.J. FV-100 versus valacyclovir for the
prevention of post-herpetic neuralgia and the treatment of acute herpes zoster-associated pain: A randomized-controlled trial. J.
Med. Virol. 2017, 89, 1255–1264. [CrossRef]
91. Abele, G.; Eriksson, B.; Harmenberg, J.; Wahren, B. Inhibition of varicella-zoster virus-induced DNA polymerase by a new
guanosine analog, 9-(4-hydroxy-2-(hydroxymethyl)butyl)guanine triphosphate. Antimicrob. Agents Chemother. 1988, 32, 1137–1142.
[CrossRef]
92. Lowe, D.M.; Alderton, W.K.; Ellis, M.R.; Parmar, V.; Miller, W.H.; Roberts, G.B.; Fyfe, J.A.; Gaillard, R.; Ertl, P.; Snowden, W.; et al.
Mode of action of (R)-9-(4-hydroxy-2-(hydroxymethyl)butyl)guanine against herpesviruses. Antimicrob. Agents Chemother. 1995,
39, 1802–1808. [CrossRef]
93. Ng, T.I.; Shi, Y.; Huffaker, H.J.; Kati, W.; Liu, Y.; Chen, C.M.; Lin, Z.; Maring, C.; Kohlbrenner, W.E.; Molla, A. Selection and
characterization of varicella-zoster virus variants resistant to (R)-9-(4-hydroxy-2-(hydroxymethy)butyl)guanine. Antimicrob.
Agents Chemother. 2001, 45, 1629–1636. [CrossRef] [PubMed]
94. Neyts, J.; Andrei, G.; De Clercq, E. The antiherpesvirus activity of H2G ((R)-9-(4-hydroxy-2-(hydroxymethyl)butyl)guanine) is
markedly enhanced by the novel immunosuppressive agent mycophenolate mofetil. Antimicrob. Agents Chemother. 1998, 42,
3285–3289. [CrossRef] [PubMed]
95. De Clercq, E.; Field, H.J. Antiviral prodrugs-the development of successful prodrug strategies for antiviral chemotherapy. Br. J.
Pharmacol. 2006, 147, 1–11. [CrossRef]
96. Tyring, S.K.; Plunkett, S.; Scribner, A.R.; Broker, R.E.; Herrod, J.N.; Handke, L.T.; Wise, J.M.; Martin, P.A. Valomaciclovir versus
valacyclovir for the treatment of acute herpes zoster in immunocompetent adults: A randomized, double-blind, active-controlled
trial. J. Med. Virol. 2012, 84, 1224–1232. [CrossRef]
97. Balfour, H.H., Jr.; Vezina, H.E.; Hogquist, R.C.; Brundage, R.C.; Anderson, B.J.; Odumade, O.A. Randomized, placebo-controlled,
double-blind trial of valomacicovir (VALM) for infectious mononucleosis (IM). In Proceedings of the 49th Annual Meeting of the
Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA, USA, 14 September 2009; p. 221.
98. Hostetler, K.Y. Alkoxyalkyl prodrugs of acyclic nucleoside phosphonates enhance oral antiviral activity and reduce toxicity:
Current state of the art. Antiviral. Res. 2009, 82, A84–A98. [CrossRef]
99. Beadle, J.R.; Hartline, C.; Aldern, K.A.; Rodriguez, N.; Harden, E.; Kern, E.R.; Hostetler, K.Y. Alkoxyalkyl esters of cidofovir
and cyclic cidofovir exhibit multiple-log enhancement of antiviral activity against cytomegalovirus and herpesvirus replication
in vitro. Antimicrob. Agents Chemother. 2002, 46, 2381–2386. [CrossRef]
100. Marty, F.M.; Winston, D.J.; Chemaly, R.F.; Mullane, K.M.; Shore, T.B.; Papanicolaou, G.A.; Chittick, G.; Brundage, T.M.; Wilson, C.;
Morrison, M.E.; et al. A Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial of Oral Brincidofovir for Cytomegalovirus
Prophylaxis in Allogeneic Hematopoietic Cell Transplantation. Biol. Blood Marrow Transplant. 2019, 25, 369–381. [CrossRef]
[PubMed]
101. Lee, Y.J.; Neofytos, D.; Kim, S.J.; Cheteyan, L.; Huang, Y.T.; Papadopoulos, E.B.; Jakubowski, A.A.; Papanicolaou, G.A. Efficacy of
brincidofovir as prophylaxis against HSV and VZV in hematopoietic cell transplant recipients. Transpl. Infect. Dis. 2018, 20, 2977.
[CrossRef] [PubMed]
102. Mullane, K.M.; Nuss, C.; Ridgeway, J.; Prichard, M.N.; Hartline, C.B.; Theusch, J.; Marin, M.H.; Larson, R.A. Brincidofovir
treatment of acyclovir-resistant disseminated varicella zoster virus infection in an immunocompromised host. Transpl. Infect. Dis.
2016, 18, 785–790. [CrossRef] [PubMed]
103. Katsamakas, S.; Zografos, A.L.; Sarli, V. Advances of Phenoxazines: Synthesis, Reactivity and Their Medicinal Applications. Curr.
Med. Chem. 2016, 23, 2972–2999. [CrossRef] [PubMed]
104. Kozlovskaya, L.I.; Andrei, G.; Orlov, A.A.; Khvatov, E.V.; Koruchekov, A.A.; Belyaev, E.S.; Nikolaev, E.N.; Korshun, V.A.; Snoeck,
R.; Osolodkin, D.I.; et al. Antiviral activity spectrum of phenoxazine nucleoside derivatives. Antivir. Res. 2019, 163, 117–124.
[CrossRef] [PubMed]
Molecules 2021, 26, 1132 34 of 34
105. Hayashi, K.; Hayashi, T.; Tomoda, A. Phenoxazine derivatives inactivate human cytomegalovirus, herpes simplex virus-1, and
herpes simplex virus-2 in vitro. J. Pharmacol. Sci. 2008, 106, 369–375. [CrossRef]
106. Plebanek, E.; Lescrinier, E.; Andrei, G.; Snoeck, R.; Herdewijn, P.; De Jonghe, S. Emimycin and its nucleoside derivatives: Synthesis
and antiviral activity. Eur. J. Med. Chem. 2018, 144, 93–103. [CrossRef]
107. Sari, O.; Roy, V.; Balzarini, J.; Snoeck, R.; Andrei, G.; Agrofoglio, L.A. Synthesis and antiviral evaluation of C5-substituted-(1,3-
diyne)-20 -deoxyuridines. Eur. J. Med. Chem. 2012, 53, 220–228. [CrossRef]
108. Liu, C.; Chen, Q.; Yang, M.; Schneller, S.W. C-3 halo and 3-methyl substituted 50 -nor-3-deazaaristeromycins: Synthesis and
antiviral properties. Bioorg. Med. Chem. 2013, 21, 359–364. [CrossRef]
109. Baszczynski, O.; Kaiser, M.M.; Cesnek, M.; Brehova, P.; Jansa, P.; Prochazkova, E.; Dracinsky, M.; Snoeck, R.; Andrei, G.; Janeba,
Z. Xanthine-based acyclic nucleoside phosphonates with potent antiviral activity against varicella-zoster virus and human
cytomegalovirus. Antivir. Chem. Chemother. 2018, 26, 3050. [CrossRef] [PubMed]
110. Wang, M.; Srivastava, P.; Liu, C.; Snoeck, R.; Andrei, G.; De Jonghe, S.; Herdewijn, P. Synthesis and antiviral evaluation of
cyclopentyl nucleoside phosphonates. Eur. J. Med. Chem. 2018, 150, 616–625. [CrossRef]
111. Bessieres, M.; Hervin, V.; Roy, V.; Chartier, A.; Snoeck, R.; Andrei, G.; Lohier, J.F.; Agrofoglio, L.A. Highly convergent synthesis
and antiviral activity of (E)-but-2-enyl nucleoside phosphonoamidates. Eur. J. Med. Chem. 2018, 146, 678–686. [CrossRef]
112. Topalis, D.; Pradere, U.; Roy, V.; Caillat, C.; Azzouzi, A.; Broggi, J.; Snoeck, R.; Andrei, G.; Lin, J.; Eriksson, S.; et al. Novel antiviral
C5-substituted pyrimidine acyclic nucleoside phosphonates selected as human thymidylate kinase substrates. J. Med. Chem. 2011,
113. Pertusati, F.; Serafini, S.; Albadry, N.; Snoeck, R.; Andrei, G. Phosphonoamidate prodrugs of C5-substituted pyrimidine acyclic
nucleosides for antiviral therapy. Antivir. Res. 2017, 143, 262–268. [CrossRef] [PubMed]
114. Krecmerova, M.; Dracinsky, M.; Snoeck, R.; Balzarini, J.; Pomeisl, K.; Andrei, G. New prodrugs of two pyrimidine acyclic
nucleoside phosphonates: Synthesis and antiviral activity. Bioorg. Med. Chem. 2017, 25, 4637–4648. [CrossRef] [PubMed]
115. Luo, M.; Groaz, E.; Andrei, G.; Snoeck, R.; Kalkeri, R.; Ptak, R.G.; Hartman, T.; Buckheit, R.W., Jr.; Schols, D.; De Jonghe, S.;
et al. Expanding the Antiviral Spectrum of 3-Fluoro-2-(phosphonomethoxy)propyl Acyclic Nucleoside Phosphonates: Diamyl
Aspartate Amidate Prodrugs. J. Med. Chem. 2017, 60, 6220–6238. [CrossRef] [PubMed]
116. Luo, M.; Groaz, E.; De Jonghe, S.; Snoeck, R.; Andrei, G.; Herdewijn, P. Amidate Prodrugs of Cyclic 9-(S)-[3-Hydroxy-2-
(phosphonomethoxy)propyl]adenine with Potent Anti-Herpesvirus Activity. ACS Med. Chem. Lett. 2018, 9, 381–385. [CrossRef]
117. Inoue, N.; Matsushita, M.; Fukui, Y.; Yamada, S.; Tsuda, M.; Higashi, C.; Kaneko, K.; Hasegawa, H.; Yamaguchi, T. Identification
of a varicella-zoster virus replication inhibitor that blocks capsid assembly by interacting with the floor domain of the major
capsid protein. J. Virol. 2012, 86, 12198–12207. [CrossRef]
118. Yasui, R.; Yoshida, C.; Yamaguchi, T.; Inoue, N. Characterization of an anti-varicella-zoster virus compound that targets the portal
protein encoded by ORF54. Microbiol. Immunol. 2017, 61, 398–402. [CrossRef]
119. Majima, R.; Shindoh, K.; Yamaguchi, T.; Inoue, N. Characterization of a thienylcarboxamide derivative that inhibits the trans-
activation functions of cytomegalovirus IE2 and varicella zoster virus IE62. Antivir. Res. 2017, 140, 142–150. [CrossRef]
[PubMed]
120. Musella, S.; di Sarno, V.; Ciaglia, T.; Sala, M.; Spensiero, A.; Scala, M.C.; Ostacolo, C.; Andrei, G.; Balzarini, J.; Snoeck, R.; et al.
Identification of an indol-based derivative as potent and selective varicella zoster virus (VZV) inhibitor. Eur. J. Med. Chem. 2016,
124, 773–781. [CrossRef]
121. Kim, J.E.; Song, Y.J. Anti-varicella-zoster virus activity of cephalotaxine esters in vitro. J. Microbiol. 2019, 57, 74–79. [CrossRef]
122. Kaoukabi, H.; Kabri, Y.; Curti, C.; Taourirte, M.; Ubis, R.J.C.; Snoeck, R.; Andrei, G.; Vanelle, P.; Lazrek, H.B. Dihydropyrimidinone/
1,2,3-triazole hybrid molecules: Synthesis and anti-varicella-zoster virus (VZV) evaluation. Eur. J. Med. Chem. 2018, 155, 772–781.
[CrossRef]
123. Gupta, A.; Dixit, B.; Stamoulas, K.; Akshikar, R. Atypical bilateral acute retinal necrosis in a coronavirus disease 2019 positive
immunosuppressed patient. Eur. J. Ophthalmol. 2020, 4941. [CrossRef]
124. Tartari, F.; Spadotto, A.; Zengarini, C.; Zanoni, R.; Guglielmo, A.; Adorno, A.; Valzania, C.; Pileri, A. Herpes zoster in COVID-19-
positive patients. Int. J. Dermatol. 2020, 59, 1028–1029. [CrossRef] [PubMed]
125. Shors, A.R. Herpes zoster and severe acute herpetic neuralgia as a complication of COVID-19 infection. JAAD Case Rep. 2020, 6,
656–657. [CrossRef]
126. Elsaie, M.L.; Youssef, E.A.; Nada, H.A. Herpes zoster might be an indicator for latent COVID 19 infection. Dermatol. Ther. 2020,
33, 3666. [CrossRef]
127. Ferreira, A.; Romao, T.T.; Macedo, Y.S.; Pupe, C.; Nascimento, O.J.M.; Fellow of the American Academy of Neurology (FAAN).
COVID-19 and herpes zoster co-infection presenting with trigeminal neuropathy. Eur. J. Neurol. 2020, 27, 1748–1750. [CrossRef]
[PubMed]
128. Saati, A.; Husayni, A.F.; Malibari, A.A.; Bogari, A.A.; Alharbi, M. Herpes Zoster Co-Infection in an Immunocompetent Patient
with COVID-19. Cureus 2020, 12, 8998. [CrossRef]

Molecules 26 01132

Uploaded by

Copyright:

Available Formats

You might also like

Molecules 26 01132

Uploaded by

Document Information

Original Description:

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Molecules 26 01132

Uploaded by

Copyright:

Available Formats

molecules

Academic Editors: Libor Grubhoffer

Molecules 2021, 26, 1132. https://doi.org/10.3390/molecules26041132 https://www.mdpi.com/journal/molecules

2. Clinical Characteristics of VZV Infections

3. Vaccination Strategies and Post-Exposure Prophylaxis

Varicella Vaccine Herpes Zoster Vaccine

• ≥ children 12 months • FDA approved: ≥50 • FDA approved: ≥50

Varicella Vaccine Herpes Zoster Vaccine

4. Treatment of VZV-Associated Diseases

vynildeoxyuridine pean countries

Penciclovir [PCV, 9-(4-hydroxy-3-hydroxymethyl-but-1-yl)guanine, Denavir® , Vectavir® ],

stoichiometry) possesses multiple enzymatic activities including DNA helicase, single-

400 mg is effective and well tolerated for treatment of HZ in immunocompetent Japanese

5. Medical Need for New Antiviral Agents to Manage VZV-Associated Diseases

5.3. Emergence of Drug-Resistant Viruses

6. Novel Anti-VZV Agents in Advanced Development

Molecules 2021, 26, 1132 14 of 35

6.1. Bicyclic Nucleoside Analogues (BCNAs)

Since omaciclovir oral bioavailability is of 17% in cynomolgus monkeys, similar to

7. Candidate anti-VZV Drugs

0.06 µM 10 µM >100 µM No activity against HCMV

HSV‐1 TK−− and

Carbocyclic nucleosides: 0.11 μM No data >300 μM Activity against HCMV, no

R = Br (E)‐ compound 18 20 μM 15 μM 35 μM Weak activity against HSV‐1,

Prodrugs of pyrimidine acyclic nucleoside analogues

Bis(aminoacid) 0.56 μM 1.69 μM 25.9 μM Activity against HSV‐1 &

Parent compound PME‐5azaC 100 μM 40 μM >200 μM Marginal activity against

0.32 μM 0.79 μM 79.2 μM Activity against HSV‐1, HSV‐

Diamyl aspartate amidate prodrugs of 3‐Fluoro‐2‐

Diamyl aspartate amidate prodrugs of 3‐Fluoro‐2‐

[(5‐Chlorobenzo[b]thiophen‐3‐yl)methyl] [(4‐chloro‐ 16.9 μM 18.3 μM >100 μM

N‐(4‐Chlorophenyl)‐5‐nitro‐3‐thienylcarboxamide (133G4) 19.3 μM No data 537 μM Activity against HCMV

Indole‐based derivatives 2.6 μM 2.0 μM >100 μM No activity against HSV‐1,

7.1.4. Carbocyclic Nucleosides: C-3 halo and 3-methyl substituted

7.1.5. Xanthine-Based Acyclic Nucleoside Phosphonates (ANPs)

7.1.6. Cyclopentyl Nucleoside Phosphonates

7.1.7. (E)-but-2-enyl Nucleoside Phosphonoamidates

7.1.8. Prodrugs of C5-Substituted Pyrimidine Acyclic Nucleosides for Antiviral Therapy

7.1.9. Prodrugs of the Pyrimidine Acyclic Nucleoside Phosphonates PMEO-DAPy and

7.1.10. Diamyl Aspartate Amidate Prodrugs of 3-Fluoro-2-(phosphonomethoxy)propyl

7.1.11. Amidate Prodrugs of Cyclic 9-(S)-[3-Hydroxy-2-(phosphonomethoxy)

7.2. Non-Nucleoside Analogues

7.2.2. 5-Chlorobenzo[b]thiophen Derivative

7.2.3. Thienylcarboxamide Derivative

7.2.4. Indole-Based Derivatives

7.2.5. Cephalotaxine Esters

7.3. Hybrid Molecules

selectivity of dihydropyrimidinone/1,2,3-triazole hybrid molecules into the herpesviridae

8. Conclusions and Perspectives

Author Contributions: Conceptualization, G.A.; writing—original draft preparation, G.A.; writing—

You might also like