Antiviral and Anti-HIV

Drugs

Trans-membranous Spike of
glycoprotein (gp41) envelope
glycoprotein
(gp120)
Host cell
protein

Reverse RNA with

transcriptase protein
surround
(p7/p9)
Lipid layer
 ANTIVIRAL AGENTS
 Antiviral agents are drugs that cure or control viral
infections.
– Unlike antibacterial drugs, which may cover a wide range of
pathogens,
– Antiviral agents tend to be narrow in spectrum,
– And have limited efficacy.
 The reason for this is the fact that viruses are obligate
intracellular parasites which use the host cell for synthesizing
viral proteins and for replication;
– Accordingly, any drug that interferes significantly with viral
replication is likely to be toxic to the host.

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Strategies for Antiviral Therapy

Any stage of viral replication can be a target for antiviral drugs.

The only requirements are:

- The stage targeted is essential for virus replication.

- The therapeutic agent is active against the virus while

having "acceptable toxicity" to the host organism.

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 Stages in Virus Replication which are Possible
Targets for Chemotherapeutic Agents

• Attachment to host cell.

• Uncoating - (Amantadine).

• Replication of viral RNA or DNA - (Nucleoside analogues).

• Synthesis of viral mRNA - (Interferon) Translation of mRNA -

(Interferon).
• Maturation of new virus proteins (Protease inhibitors).

• Release.

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5
 Classification of Antivirals

1. Antivirals effective against influenza virus.

2. Antivirals effective against herpes virus.

3. Antivirals effective against respiratory syncytial

virus.

4. Antivirals effective against hepatitis C and B.

5. Antivirals effective against HIV virus.

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 1. Antiviral Agents Effective Against Influenza
Viruses

A. Agents Effective Against Influenza Virus Type A

Adamantane Derivatives

i. Amantadine HCl (Adamine)

ii. Rimantadine HCl (Flumadine)

NH2.HCl H3C NH2 .HCl

1-Adamantanamine -Methyl-adamantanemethylamine
Adamantane 7
hydrochloride hydrochloride
• The clinical usefulness of amantadine and rimantadine is limited to the
prevention and treatment of influenza A virus infections.
• When they are taken orally, 24-48 hours after the onset of illness, they
reduce the duration of fever and other symptoms by preventing invasion of
additional cells.
• Both amantadine and rimantadine can cause central nervous system (CNS)
and gastrointestinal side effects.
• However, the incidence of CNS side effects (e.g., nervousness, anxiety,
disorientation, and insomnia...) is higher among persons taking amantadine
than among those taking rimantadine.
 Rimantadine also has a longer duration of action.

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MOA
• The two drugs inhibit the early stages of viral replication, blocking the
uncoating of the viral genome and the transfer of nucleic acid into the host
cells.
• Amantadine inhibits also virus particle penetration into the host cells.

B) Agents Effective Against Virus Influenza Types A and B Neuraminidase

Inhibitors (Sialic Acid Analogs)

i. Zanamivir (Relanaze)

ii. Oseltamivir (Tamiflue)

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 Zanamivir (Relanaze) Oseltamivir
(Tamiflue)
HO OH
H
HO O O COOC2H5
H3CCONH COOH
3
4
5
HN
HN
NH2 NH2 . H3PO4
N O
H

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• The neuraminidase inhibitors, zanamivir and oseltamivir, are chemically
related drugs that have activity against both influenza A and B viruses.
• Zanamivir is an orally inhaled powdered drug that is approved for
treatment of influenza in persons aged 7 years and older.
• Oseltamivir is an orally administered capsule or oral suspension that is
approved for treatment of influenza in persons aged 1 year and older.
• Oseltamivir is also approved for chemoprophylaxis of influenza in
persons aged 13 years and older.
• Oseltamivir is an ethyl ester prodrug requiring ester hydrolysis for
conversion to the active form, oseltamivir carboxylate

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MOA
 Influenza viruses are surrounded by a protein coat and a lipid
envelope. Embedded in the lipid membrane are two surface
glycoproteins:
-Hemaglutinin (HA) is an enzyme important for
binding viruses to target cell receptor via a terminal
sialic acid residue.
-Neuraminidase (NA) an enzyme involved in various
activation of influenza viruses.

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• NA is found in both influenza A and B and is thought to be
involved in catalytically cleaving glycosidic bonds
between terminal sialic acid and an adjacent sugar.
 The cleavage of sialic acid bonds facilitates the spread of
viruses and as a result increases the infectiveness or
pathogencity of the virus.

• NA inhibitors interfere with the spread of the infection by

blocking sialic acid bonds cleavage.
 This effect results in viral aggregation at the host cell surface
and reduces the number of viruses released from the infected
cell. 13
2. Antiviral Agents Effective Against Herpes Virus
The family of herpes virus includes:

A. Herpes simplex types 1 and 2 (HSV1, HSV2), Varicella Zoster

(VZV) and Epstein Bar (EBV).

B. Cytomegalovirus (CMV).

A) Agents Effective Against HSV1 and 2, VZV and EBV

 Drugs in this class are Nucleoside analogues with sugar
modification. They resemble natural nucleosides, but have an
incomplete ribose group. They act as DNA polymerase inhibitors.

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Basics: Nucleotides are the building blocks of DNA

Only in RNA,
not DNA
16
 i. Acyclovir (Zovirax) ii. Valacyclovir HCl
O O
N N
HN HN
N NH2 . HC l
H2N N H2N N
N O C H(C H3)2
OH O
H
O O

9-[(2-Hydroxyethoxy)methyl]guanine

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• Acyclovir is a synthetic analog of the normal metabolite
2’-Deoxyguanosine.

Acyclovir is most active against HSV but also has

activity against VZV with little activity against EBV and
no activity against CMV
• Valacyclovir is a valine ester of acyclovir that is well
absorbed. Its bioavailability is 2-5 greater than acyclovir.
So lower dose is possible, at less frequent intervals. It is
used for the treatment and suppression of genital herpes
infection. 18
iii. Famiciclovir (Famvir)

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Famiciclovir is the prodrug of penciclovir which is the active form
and a guanosine analog.
• It has a very high bioavailability of 77%. It is converted into
penciclovir by a two step process.
• The first step occurs in the gut and the second step in the liver and it
has a long half life in the gut than acyclovir.
• It acts as an inhibitor of viral DNA polymerase.

• At present famiciclovir is licensed for the treatment of shingles and

also used for the treatment and suppression of genital herpes.

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MOA
• They are phosphorylated to the monophosphate by viral
thymidine kinase and then to the di- then triphosphate by a host
cell kinase.
• The triphosphate form of the drug blocks DNA replication of viral
DNA by competitive inhibition of viral DNA polymerase and
incorporation and termination of the growing viral DNA chain.
– Chain termination occurs because the drug triphosphate lacks
the 3-hydroxy group of cyclic sugar.

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Selectivity of Action

-These drugs reduce DNA synthesis in virus-infected cells without affecting the active
replication of uninfected cells because:

-Viral thymidine kinase phosphorylates the drug over 100 times faster than host cells
(differential toxicity).

-Acyclovir triphosphate competitively inhibits viral DNA polymerases, and to a much

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Other Drugs Used as Topical Applications for Herpes

Trifluridine O Idoxuridine
R
HN
)R = CF3( )R = I(
O N
O
HO

HO

Trifluridine (Viroptic) (R=CF3) 2'-deoxy-5-(trifluoromethyl) uridine

Idoxuridine (Herplex) (R = I) 2'-deoxy-5-iodouridine

 These are pyrimidine analogs with base modification. Because of their

mutagenic and teratogenic effects following systemic administration, idoxuridine
and trifluridine are only suitable for topical use.
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 B) Agents Effective Against Cytomegalovirus (CMV)

i. Ganciclovir (Cytovene) 9-[1,3-Dihydroxy-2-propoxymethyl]guanine

• Ganciclovir is a deoxyguanosine analog that differs from acyclovir in having
an additional hydroxymethyl group on the acyclic side chain.
• It is the preferred drug for treating (CMV) infections in patients with acquired
immune deficiency syndrome (AIDS) or other immunodeficiencies.
• This agent has inhibitory activity against all herpes viruses but its unique
characteristic is the potent inhibition of CMV replication.
• It has very poor oral bioavailability (3 percent), and, therefore, mostly given
intravenously .

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MOA
• It is an acyclic guanine nucleoside analog and is activated to the
nucleoside triphosphate that incorporates into new viral DNA and
inhibits DNA polymerase.
• CMV is deficient in thymidine kinase this is why acyclovir has no
activity against CMV.
• CMV may phosphorylate this drug by using UL97 gene product.
 Selectivity is achieved because the viral polymerase has 30

times greater affinity for ganciclovir than the host enzyme .

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ii. Foscarnet (Foscavir)
 It is trisodium phosphonoformate

• It is the second drug used in the treatment of CMV infections,

particularly CMV retinitis, in immunocompromised patients.
• It is given intravenously, and it has proved effective in delaying
progression of CMV retinitis.

P 3 Na
O COO
O
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MOA
• It is an inorganic pyrophosphate analog that works by reversibly
blocking the pyrophosphate binding site on viral DNA
polymerase, thereby terminating chain elongation.
– Unlike nucleoside analogs, foscarnet does not need to be
activated by cellular or viral kinases.

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 3. Antiviral Agents Effective Against Respiratory Syncytial
Virus

Ribavirin (Virazole)
 1β-D-Ribofuranosyl-1H-1,2,4-triazole-3-carboxamide

• Ribavirin is a synthetic triazole nucleoside in which both the

base and the D-ribose sugar are necessary for antiviral activity .
O
H2N
N
N
N
O
HO

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HO OH
• Ribavirin inhibits the in vitro replication of a wide range of RNA
and DNA viruses but it is approved only for the treatment of
respiratory syncytial virus (RSV) infection in infants.
• The drug is administered as a small-particle aerosol (particle
diameter, 1 to 3 µm) so that it can reach the lower respiratory
tract.
• Aerosolized ribavirin treatment results in more rapid cessation of
viral shedding and resolution of clinical symptoms without signs
of systemic toxicity.

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MOA
• The antiviral mechanism of action of ribavirin is not fully defined,
but relates to the ability of cells to take up ribavirin and to form
active triphosphate derivatives.
• Intracellular phosphorylation to the mono-, di-, and triphosphate
derivatives is mediated by host cell enzymes.
• Ribavirin monophosphate inhibits inosine monophosphate
dehydrogenase which is involved in the synthesis of guanosine
monophosphate and the triphosphate is an inhibitor of viral RNA
polymerase

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4. Antiviral Agents Effective Against Hepatitis B and C
Interferons
• Interferons are a family of cytokines discovered in the late
1950s,with broad spectrum antiviral and potential anticancer
activity making them biologic response modifiers (BRM).
• There are three main types of interferons, alpha, beta, and
gamma interferons which differ both structurally and
antigenically.
• Alpha interferon is produced mainly by certain leukocytes, beta
interferon by epithelial cells and fibroblasts, and gamma
interferon by T and natural killer cells. 31
• Interferon consists of small proteins with molecular weights ranging
from 20,000 to 160,000.
• Interferons are released from eukaryotic cell types in response to
virus infection, and other biological inducers.
• The important role played by interferons as a defense mechanism is
supported by three types of experimental and clinical observations:
– For many viral infections, a strong correlation has been
established between interferon production and natural recovery.

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 – Inhibition of interferon production or action enhances the
severity of infection.
– Treatment with interferon protects against infection.

• For many years the supply of human interferon for

research was limited by costly extraction techniques.
• In 1980, however, the protein became available in
greater quantities through genetic engineering
(recombinant DNA technology)
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 MOA of Interferons
• Increased expression of Class I and Class II MHC glycoproteins,
thereby facilitating the recognition of viral antigens by the immune
system.
• Immunoregulatory effects - activation of cells with the ability to
destroy virus-infected targets; these include NK cells and
macrophages.
• Direct inhibition of viral replication.
– It inhibits the transcription and translation of mRNA into viral
nucleic acid and protein.
– It may also act by blocking synthesis of a cleaving enzyme
required for viral release.
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Interferon inducers
• These are chemical compounds that induce the production and
release of interferon in humans. Among interferon inducers
are:

Statolon
• A double-stranded RNA produced in penicillium stoloniferum
culture.

Ampligen
• A polynucleotide derivative that was found to have in-vitro
anti-HIV activity.
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Clinical Application
• Recombinant alpha and beta interferons are now available and
have been used for the treatment of chronic hepatitis C (plus
ribavirin) and chronic hepatitis B. Other uses of interferons
include the treatment of influenza, herpes zoster and genitalis,
common cold infections and cancers such as breast cancer and
lung carcinoma.

Disadvantage of Interferon Treatment

GIT problems.

CNS side effects.

Hypotension, anorexia and weight loss. 36

 5. Antiviral Agents Effective Against HIV

• Although, billions of dollars have been spent on research and

development of anti–AIDS drugs, the disease remains uncontrolled.
• Over 30 million people infected worldwide with HIV and
approximately 5 million cases are reported in the United States.
• Therapy of HIV is complicated by the ability of the virus to mutate
leading to rapid drug resistance.
• Although a number of substances with in vitro anti-HIV activity
have been described, only a few drugs exhibit anti-HIV activity in
vivo at tolerable toxicities.
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HIV target
• Several different kinds of cells have proteins on their surface that
are called CD4 receptors.
• HIV searches for cells that have CD4 surface receptors, because
this particular protein enables the virus to bind to the cell.
• Although HIV infects a variety of cells, its main target is the T4-
lymphocyte (also called the "T-helper cell"), a kind of white
blood cell that has lots of CD4 receptors.

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• The T4-cell is responsible for warning your immune system
that there are invaders in the system.
• When the number of CD4 cells drops to a certain level
because of HIV infection, the body's immune system
weakens.
– As a result, organisms such as fungi, viruses, and parasites
can cause serious infections in people with HIV.
• When these infections occur, or when the number of CD4
cells drops below a certain level, a person with HIV infection
is said to have AIDS. 39
40
HIV Types

Two types of HIV can be distinguished genetically and antigenically.

HIV-1 is the cause of the current pandemic.

HIV-2 is found in West Africa but rarely elsewhere and causes AIDS
much more slowly than HIV-1.

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 Classes of Antiretrovirals
• Fusion inhibitors
– Prevents fusion of the virus into a CD4 cell by
preventing conformational change needed to allow
virus to enter a CD4 cell
• Nucleoside/tide reverse transcriptase inhibitors
(NRTIs) or nukes
– Mimic naturally occurring nucleosides
– Block viral DNA construction as they deceive reverse
transcriptase
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42
 Classes of Antiretrovirals (2)
• Non- nucleoside reverse transcriptase inhibitors
(NNRTIs) or non-nukes (Nevirapine or Efavirenz)
 Bind to the reverse transcriptase enzyme
• Integrase inhibitors (Raltegravir, Elvitegravir)
– Inhibit integration of proviral DNA into the host DNA
• Protease inhibitors (PIs) (Lopinavir)
– Prevents cleavage of the protease chain

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A) Nucleoside Analogs Reverse Transcriptase Inhibitors (NRTI)

• Reverse transcriptase enzyme (RT) is one which reverses the

usual information flow in a cell to opposite order.
– i.e. DNA is produced on an RNA template.

• The synthesis of viral DNA under the direction of (RT) requires

availability of purines and pyrimidines nucleosides and
nucleotides. Therefore the aim is to design drugs which mimic
natural nucleosides but with a variety of chemical
modifications.

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 Among these drugs are:
ii. Stavudine (D4T) (Zerit)
i. Zidovudine (AZT) (Retrovi) O
CH3
O
HN
CH3
HN
O N
O
O N HO
O
HO

N3 Dideoxy -2’,3’-didehydrothymidine-’3,’2

Azido- 2',3’-deoxythymidine-’3

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 Lamivudine (3TC) Didanosine (DDI)
O
NH2 N NH
N
N N
O O
N
O
HO
S
HO
S

.Deoxy -3’-thiacytidine. -2 2’,3’-Dideoxyinosine

46
• Zidovudine was the first antiviral agent shown to have beneficial
effect against HIV infection.
• However, after prolonged use, AZT-resistant strains rapidly
appears which limits the effect of AZT.
• It is an analog of thymidine in which the azido group is
substituted at the 3 carbon atom of the dideoxyribose moiety.
• Stavudine differs in structure from thymidine by replacement of
the 3’hydroxyl group with a hydrogen atom and a double bond in
the 2’and 3’ positions of deoxyribose ring.

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• Lamivudine is an analog of 2’-deoxycytidine in which
the 3’-methylene group of deoxyribose ring is replaced
with a sulfur atom.
• Didanosine is a purine dideoxynucleoside which is an
analog of inosine .

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 MOA
• They are first bioactivated to triphosphate by cellular kinase. These
phosphates act as:
– Competitive inhibitor of viral reverse transcriptase.

– Chain terminators.

• They are incorporated into viral DNA and viral DNA synthesis is
terminated because these drugs lack a 3’–OH group, consequently
no more phosphodiester bonds could be formed.

Selectivity of Action

These drugs are less susceptible to mammalian DNA polymerase. Viral

reverse transcriptase is 100 times more susceptible to inhibition by
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zidovudine triphosphate than host cellular DNA polymerase.
 NRTI Adverse Effects
Zidovudine Abacavir Lamivudine Emtricitabine

• Bone marrow •Hypersensitivity • Generally well- • Hyperpigmentation

suppression reaction: fever, tolerated of palms and soles
(anemia/ rash, fatigue,
neutropenia) malaise, nausea,
• Nausea vomiting, diarrhea,
• loss of appetite,
Nail
pharyngitis
discoloration

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 NRTI Adverse Effects

Stavudine Didanosine Tenofovir

• Peripheral • Pancreatitis • GI upset

neuropathy • Peripheral • Flatulence
• Pancreatitis neuropathy • Nephrotoxicity
• Increased • Diarrhea
triglycerides

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B. Non Nucleoside Analogues Reverse Transcriptase
Inhibitors (NNRTI)

• FDA has approved NNRTI.

• They should not be used as monotherapy but they are used with
NRTI to obtain synergistic activity in decreasing viral load and
increasing CD4+ cell counts.

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i. Nevirapine ii. Efavirenz

H O F3C C C
CH3
N Cl
O

N N N N O
H

benzooxazinone derivative
A dipyridodiazepinone derivative

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MOA
• These drugs noncompetitively inhibit viral RT,
presumably by binding to a site other than the nucleoside
and template binding sites (allosteric site).
• This interaction between the NNRTI and the HIV-1 RT
produces a conformational change that results in the
inactivation of the viral RT.
• Toxicity includes rash and CNS toxicity as dizziness,
insomnia and impaired concentration.
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C. HIV Protease Inhibitors
• When viral RNA is translated into a polypeptide sequence,
that sequence is assembled in a long chain that includes
several individual proteins (reverse transcriptase, protease,
integrase).
• Before these enzymes become functional, they must be cut
from the longer polypeptide chain.
• Viral protease cuts the long chain into its individual enzyme
components which then facilitate the production of new
viruses.
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56
• Inhibitors of this viral protease can be used to fight HIV
infection.
– By blocking the ability of protease to cleave the viral
polypeptide into functional enzymes, protease inhibitors
interfere with continued infection.

• Most current protease inhibitors are complex

peptidomimetic compounds with poor aqueous solubility,
low bioavailability and short plasma half-lifes.

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 N OH OH
Indinavir H
N
N
N
CH3
O
O N CH3
H
CH3

• The complexity of these agents not only contributes to their high

cost but also increases the potential for unwanted drug
interactions.

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 PI Adverse Effects
Amprenavir/fos-amprenavir GI intolerance, rash, oral paresthesias

Atazanavir Hyperbilirubinemia
Indinavir Nephrolithiasis, hyperbilirubinemia

Lopinavir/ritonavir Nausea, diarrhea, pancreatitis

Nelfinavir Diarrhea
GI intolerance, paresthesias, asthenia,
Ritonavir
taste perversion, hepatitis
Saquinavir GI intolerance
GI intolerance, hepatitis, rash,
Tipranavir
intracranial hemorrhage
Darunavir GI intolerance, rash
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Thank
You !

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