Antivirals - HIV, Hepatitis, Influenza, Herpes Treatment (Note) Atf

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Last edited: 7/4/2022
6. ANTIVIRALS | HIV, HEPATITIS, INFLUENZA, HERPES TREATMENT

Antivirals | HIV, Hepatitis, Influenza, Herpes Treatment Medical Editors: Aldrich, Ana, Sarah & Juhi
OUTLINE
I) ANTIRETROVIRAL THERAPIES - (D) VIRAL POLYPEPTIE PROCESSING - II) INFLUENZA MEDICATIONS II. HERPES VIRUS
PROTEASE INHIBITOR
HIV TREATMENT (A) LIFE CYCLE LIFE CYCLE
(E) VIRAL PART ASSEMBLY (B) DRUGS ANTI HERPES DRUGS
OVERVIEW (F) HIGLY ACTIVE ANTIRETROVIRAL (C) ADVERSE EFFECTS & CI
(A) VIRAL FUSION - FUSION/ENTRY THERAPY (HAART REGIMENT) V) SUMMARY
INHIBITOR (A) NRTI’ S (ZALES TD) III) HBV MEDICATIONS VI) REVIEW QUESTIONS
(B) VIRAL REVERSE TRANSCRIPTION – (B) NNRTI (-VIR-) (A) LIFE CYCLE
REVERSE TRANSCRIPTASE INHIBITOR (C) I NTEGRASE INHIBITORS (-TEGRAVIR) (B) DRUGS VII) REFERENCES
(NRTI & NNRTI) (D) PROTEASE INHIBITORS (-NAVIR) IV) HEPATITIS C
(C) VIRAL DNA INTEGRATION TO HOST LIFE CYCLE
CELL – INTEGRASE INHIBITOR (-TEGRAVIR) ANTI HCV DRUGS
I) ANTIRETROVIRAL THERAPIES - HIV TREATMENT
OVERVIEW
● Antiretroviral therapies
● HIV is a type of retrovirus
o Retroviruses are basically viruses that take RNA
→ convert into DNA
o They attack our immune system, particularly T
helper cells (CD4+ cells)
(A) VIRAL FUSION - FUSION/ENTRY INHIBITOR

● When HIV bind onto our T helper cells
(1) Enfuvirtide
o They utilize very specific types of proteins to gain its
fusion and entry into the actual host cell ● Inhibits the actual entry of the viral RNA into the host cell
▪ GP41 ● It won’t allow for the GP41 on the HIV virus to bind
▪ GP120 with the CD4
o If that doesn’t bind, we won’t allow for this to
● These proteins are integral to HIV virus
fuse/enter and release the viral RNA to the host cell
o Allow for it to bind onto host cell’s receptors
o What are those host cell receptors that it needs to (2) Maraviroc
bind to?
▪ GP41 binds to CD4 protein ● CCR5
▪ GP120 binds to CCR5 and CXCR4 o Very important
• CCR5 and CXCR4 are proteins found in most o Remember not all particular types of T helper cells will
express CCR5 which the HIV will bind to
of the T helper cells
▪ Only some people with the genotype for this
• CCR5 is very important to remember ▪ We have the test for this in order to use this
o Not all particular types of T helper cells particular drug
will express CCR5
● Maraviroc prevents the virus from docking into the cell
● Once the actual virus utilizes these proteins o Maraviroc will basically inhibit GP120 from
o It then fuses with the actual proteins on the host interacting with CCR5 receptor
cell o Therefore, virus can’t dock and release RNA into the
▪ And it gets shuttled into the actual host cell actual host cell
• Releases its RNA
o In short, it allows for the entry of the actual virus
into the host cell
● We can actually try to have drugs that can really prevent
this fusion and entry of the viral RNA into the host cell
Antivirals | HIV, Hepatitis, Influenza, Herpes Treatment ANTIBIOTIC PHARMACOLOGY: NOTE #6. 1 of 16
(B) VIRAL REVERSE TRANSCRIPTION – REVERSE TRANSCRIPTASE INHIBITOR (NRTI & NNRTI)
● Once the RNA inside the host cell
o The virus also releases other type of protein into the host cell
when it fuses → reverse transcriptase
• Generally, transcription is generally we take DNA
and make RNA
• If it’s reversed, we’re taking RNA and making RNA
● So, in this process
o We take and use this enzyme and convert RNA over a process
and make DNA
o This is going to be reverse transcription process
● Why is this significant?
o Because now we have viral DNA that we can try to
incorporate it into the host cell’s DNA
▪ T helper cell’s DNA in this case
● What if we have drugs that could inhibit the reverse
transcriptase?
o If we inhibit it, we won’t be able to take RNA → make DNA
▪ Can’t incorporate into the host cell
▪ Can’t use the host cell’s nuclear machinery to make proteins
and viral RNA molecules
(1) NRTI’s (Nucleoside reverse transcriptase inhibitor) (2) NNRTI’s (Non-nucleoside reverse transcriptase
(ZALES TD) inhibitors) (-vir-)
(i) Drugs (i) Drugs

● Zidovudine ● Nevirapine
● Abacavir ● Efavirenz
● Lamivudine ● Etravirine
● Emtricitabine ● Delavirdine
● Stavudine
● Tenofovir Additional note
● Didanosine ● There’s a “vir” in the center of the name
Mnemonics: ZALES TD AfraTafreeh.com

● See how the little reverse transcriptase has a little like
● Most important one because it’s the hallmark / basic pocket around its shoulder
foundation of highly active antiretroviral therapy o Allosteric site → little pocket in the picture
● In order to be able to take this HIV RNA to make DNA
● These drugs will actually bind onto the allosteric site
o It’s going to utilize reverse transcriptase enzyme
o It changes the shape of the enzyme
● Now in order to make DNA, we need nucleotides ▪ It doesn’t allow for the enzyme to be able to work
● When we read the RNA strand as well as it should
o We’re going to use particular nucleotides that we
● Remember the job of the enzyme
have around on the RNA strand
o Take the RNA → read it → grab nucleotides and
o And add accordingly to the complementary base
make DNA
and make DNA from RNA strand
● If we utilize these particular drugs to bind to this allosteric
● Reverse transcriptase is not smart enough to be able to
site
recognize the difference between a real nucleotide and
o We don’t allow for the enzyme to have a particular
a nucleoside reverse transcriptase inhibitor
structure that allows for it to properly do these
● So, reverse transcriptase grabs a nucleoside reverse
processes
transcriptase inhibitor
▪ Read the DNA → grab nucleotides → make new
o And adds it onto the growing DNA strand that we’re
DNA
trying to build off of this RNA
Quick recap
o When it does that, they can’t add any more
nucleotides to that afterwards (1) NRTI (ZALES DT)
▪ Because the nucleoside reverse transcriptase
● Acts as a kind of like a nucleotide
actually stops any more DNA formation from o And then when we add it we terminate the formation of
this RNA template further DNA
o Because it won’t allow for further DNA to be formed
Quick recap
(2) NNRTI (-vir)
● These particular drugs are going to inhibit the reverse
transcriptase from taking RNA and making DNA by ● Allosteric inhibitors
stopping the growing DNA template ● Binds onto a particular site
o By acting like a nucleotide even though it’s not o Inhibiting the reverse transcriptase enzyme from being
o It will terminate the actual formation of DNA off of this able to properly function and taking RNA and making
RNA template strain DNA
2 of 16 ANTIBIOTIC PHARMACOLOGY: NOTE #6. Antivirals | HIV, Hepatitis, Influenza, Herpes Treatment
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(C) VIRAL DNA INTEGRATION TO HOST CELL – INTEGRASE INHIBITOR (-TEGRAVIR)
● If we have a drug category that could work to inhibit
(i) Drugs integrase enzyme
● Dolutegravir o We’re not allowing for the actual viral DNA to be
● Raltegravir incorporated into the host cell DNA
● Elvitegravir
● Why viral DNA integration is a problem?
o If we incorporate the viral DNA into the host cell DNA
Additional note
o Every time we try to replicate this DNA
● There’s “-tegravir” in every single name
▪ We’re replicating the actual viral DNA
o Every time we transcribe this DNA
● From here, the DNA of HIV will then taken up into the ▪ We’re transcribing the viral DNA to make more viral
host cell’s nucleus RNA
o Remember there’s host’s DNA ● So, we need drugs that can inhibit this process
Integrase
● A particular enzyme that takes and finds a particular site
on the host DNA and makes cut
o It then takes the actual viral DNA and incorporate it
into the actual host DNA
o We’re going to have kind of mixture of viral DNA
and actual host cell DNA
● What if we have a drug category that could work to be
able to inhibit?
(D) VIRAL POLYPEPTIE PROCESSING - PROTEASE INHIBITOR
(i) Drugs Polypeptide processing by protease

● Atazanavir ● Now, we make these particular proteins utilizing the
● Darunavir actual viral RNA
● Indinavir o Once we make these, we’re making polyproteins
● Lopinavir ▪ Clumps of proteins
● Nelfinavir
● Saquinavir ● What we need to do is to utilize a very specific enzyme
● Tipranavir called protease
● Ritonavir ● Proteases take and cleave the actual polyprotein
(Gag-Pol polyproteins)
Additional note o So that we can make a lot of different types of
● There’s “-navir” in every single name structural and functional proteins
▪ Proteins that are going to be important for the
actual viral structure as well as other particular
Transcription process
types of enzymes
● Read the actual DNA and that includes the viral DNA and
If we inhibit these proteases
transcribe
o When we transcribe, we’re going to transcribe some ● They won’t be able to take the polyproteins that were
of the viral DNA → make viral RNA translated
● Now we’re going to have some viral RNA o They won’t be able to cleave them
● What happens is, when we make some of the RNA o If they can’t cleave them
o These RNA are going to go out into the cytoplasm ▪ They won’t be able to make any structural and
and find some ribosomes functional proteins that make up the actual
▪ When it goes and binds onto these ribosomes structure of the virus
▪ It will then use the ribosomes to undergo ● They won’t be able to use the particular protein to run it
translation through the Golgi apparatus and then use to make
Quick recap particular virus proteins
● The process where we take the actual DNA and viral DNA o They won’t have
to make more RNA → transcription ▪ Core proteins
● The process where we take the actual viral RNA and then ▪ Capsular proteins
try to make proteins as a result of it is called translation ▪ Enzymes inside the virus
▪ GP proteins on the surface
● In short, they can’t make new virus
(E) VIRAL PART ASSEMBLY
● Some of the viral RNA is going to be taken into the Golgi apparatus
o In combination of these types of proteins that we made from it
o And then we’re going to incorporate the actual RNA into the virus
● Then we’re going to put into put into a vesicle from the Golgi apparatus and then have it
move to the actual cell membrane where it will fuse with the cell membrane
o And exocytosis all of these viruses and release it out into the actual interstitial fluid or
vascular system
▪ To go and infect other cells
(F) HIGLY ACTIVE ANTIRETROVIRAL THERAPY (HAART REGIMENT)

● If we utilize combination of some of these drugs to inhibit particular parts of this actual life cycle of the HIV
o We can potentially prevent this viral replication and continual spread of the virus
HAART regiment (Highly Active Antiretroviral Therapy Regiment)
● Based upon the foundation of NRTI ● These two fusion/entry inhibitor drugs are adjuncts that
o We need at least two of those NRTIs to be able to we can add on to this particular therapy
perform this process no matter what
o We can pick any one of those above (i) Maraviroc
● We can add on one of the other agents ● The reason we would add on Maraviroc is they have
o Remember the utilization of one of those depends CCR5 receptor
upon the side effects or the adverse effects and o We can use this in HIV resistant strand especially to
contraindications that we want to avoid NRTI’s
Baseline HAART regiment o But particularly it’s an add-on if they have CCR5+
● 2 NRTI’s + NNRTI receptor
● 2 NRTI’s + Integrase inhibitor ▪ If they’re not positive, it’s not going to provide any
● 2 NRTI’s + Protease inhibitor actual additional benefit
Adjunct therapy (ii) Enfuvirtide

± Maraviroc ● Add this on HIV-resistant strands that are specifically
± Enfuvirtide
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● The choices of which one of these we pick depend upon
resistant to NRTI’s
the HIV genotype

o But it also depends upon the actual adverse effects
that we’re trying to avoid or contraindication
ADVERSE EFFECTS AND CONTRAINDICATIONS
● Obviously important whenever we’re getting ready to put a patient on one of these medications
o It’s important to think about the medical history and things that might actually deter us from using this particular drug and try
another one
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(A) NRTI’S (ZALES TD)
• Backbone of the HAART (highly active antiretroviral therapy)

o If we notice, there’s always two of those with 1 integrase or 1 protease
Mitochondrial toxicity Pancreatitis
● Remember mitochondria is so important for a lot of ATP ● Mnemonic to remember all of the particular causes of
formation pancreatitis
o I GET SMASHED
(i) Myopathy o D = drugs
● Super crucial when it comes to muscle being able to ▪ Stavudine
function ▪ Didanosine
o If we don’t have ATP, we can form myopathy Nephrotoxicity
(ii) Peripheral neuropathy ● Can lead to acute kidney injury
● Alter peripheral neurons → peripheral neuropathy ● Drugs
o Unknown mechanism o Tenofovir
▪ Technically not a nucleoside reverse transcriptase
(iii) Hepatic steatosis inhibitor
▪ It’s a nucleotide reverse transcriptase inhibitor
● Fatty acid oxidation
→ only one
o So we take particular fatty acids and we oxidize them
into Acetyl-CoA in the mitochondria Bone marrow suppression
● If we cause mitochondria toxicity ● It drops the number of red blood cells and neutrophils
o We can’t perform fatty acid oxidation o Anemia and neutropenia
● So what happens is the fat builds up inside of particular ● Drugs
issues → liver o Zidovudine
o If we have lots of fats building up in the liver →
hepatic steatosis Hypersensitivity reaction
● The drug may actually interact with particular type of mast
(iv) Lactic acidosis cells
● Pyruvate is supposed to get taken up into the o Leads to massive histamine response that causes
mitochondria and convert it into Acetyl-CoA ▪ Nausea
o If the mitochondria isn’t allowing for the pyruvate to ▪ Vomiting
get converted into Acetyl-CoA because of the toxic ▪ Diarrhea
effect ▪ Abdominal pain
o What it does is pyruvate get converted into lactic acid ▪ Rash
→ lactic acidosis ▪ Fever
▪ Respiratory failure
● Drugs
o Abacavir
● There are certain patient populations that are susceptible
to this
o So we want to check HLA-B5701
● Generally, the patients who have this type of HLA
hypersensitivity genes
o Are at high risk of a hypersensitivity reaction
(B) NNRTI (-VIR-)
(1) Hepatotoxicty (3) Teratogenic effect
● Common one ● We don’t want to give this to patient if they’re pregnant
● It may bump up their LFT ● Drugs
● We see this more specifically in o Efavirenz
o Efavirenz o Delavirdine
o Nevirapine
(2) CNS toxicity
● Vivid-like-dreams
● We see this primarily in efavirenz
(C) INTEGRASE INHIBITORS (-TEGRAVIR) (D) PROTEASE INHIBITORS (-NAVIR)
(1) Rhabdomyolysis & myoglobin in the urine

● Increase in CK
● Kidneys will take a lot of that myoglobin and put a ton of
myoglobin inside the urine
o Myoglobin in the urine
(1) Crystal-induced nephropathy
● It can actually lead to tubular necrosis → lead to acute
kidney injury
● Indinavir
o It has been shown to be able to increase the
formation of crystal
o Can cause acute necrosis and destruction of the
actual kidney tubules → leading to acute kidney injury
(2) Lipodystrophy
● All of these drugs have the ability to produce
lipodystrophy
● Fat accumulation and it can produce kind of like a
Cushing syndrome
o Buffalo hump
AfraTafreeh.com o Swollen moon face
o Hyperglycemia (high level of glucose)
▪ Most of these drugs will inhibit GLUT transporter
▪ GLUT transporters are supposed to take and
shuttle glucose into our actual cells
• So, they want to bring glucose into our cells
▪ But these drugs will inhibit these GLUT
transporters
▪ If we inhibit these, we can’t take glucose into the
cell
• The glucose builds up inside the
bloodstream
(3) CYP450 inhibitor
● CYP450 enzymes involved in biotransformation in drug
metabolism
▪ Adding on different typs of molecules like
glucuronates, etc.
▪ Making them more pole
● Ritonavir inhibits CYP450 enzymes
o If we inhibit them, we develop higher level of that
drug concentration
o That could be concerning depending upon what type
of drug we’re taking
▪ If we’re taking like warfarin, we’ll have higher risk
of having bleeding
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II) INFLUENZA MEDICATIONS

(A) LIFE CYCLE
(1) Structure of the virus (iii) Transcription
(i) Hematogglutinin (HA) a. The NP travels to the nucleus where it is transcribed
into mRNA
● Located on the virus envelope.
b. All genomic segments are transcribed into 5’-
● Viral attachment protein
capped, 3’-polyadenylated (polyA) mRNA for
o Binds to sialic acid on epithelial cell surface receptors.
individual proteins by endonucleases
● Fusion protein. i. Exception: M1, M2 and NS1, NS2 proteins are
differentially spliced
(ii) Neuraminidase (NA) → Two different mRNAs are produced.
● Located on the virus envelope.
● Cleaves sialic acid and promotes virus release.
(iii) Membrane protein (M2)

● Forms a proton channel in membranes and promotes
uncoating and viral release.
(iv) Matrix protein (M1)

● Lines the inside of the virion and promotes assembly.
(v) Nucleocaspid protein (NP)
(iv) Translation
a. The mRNAs are translated into proteins and
glycoproteins in the cytoplasm.
b. The HA and NA glycoproteins are processed by the
endoplasmic reticulum and Golgi apparatus.
(2) Replication (v) Replication

a. The negative-sense RNA genome is replicated in the
nucleus utilizing RNA polymerase.
(i) Binding
a. HA binds to sialic acid on respiratory cell surface
(vi) Assembly
glycoproteins a. The HA and NA glycoproteins are delivered to M2
b. The virus is internalized into a coated vesicle and containing plasma membrane
transferred into an endosome. i. M1 protein associates with the glycoprotein tails
and the RNP nucleocapsid associates with
the matrix protein.
(ii) Uncoating
(vii) Budding exit
a. M2 protein channel acidifies the region between the
M1 protein and nucleocapsid, releasing it to the a. The virus acquire its envelope as it buds away from
cytoplasm. the cell by an insertion of the HA in its membrane,
approximately 8 hours after infection.
(B) DRUGS (C) ADVERSE EFFECTS & CI
(1) Uncoating Inhibitor Amantadine
→ The only one that is likely to cause side effects
(i) Amantadine
→ Primarily utilized in influenza type A (i) Ataxia
(2) Endonuclease Inhibitor (ii) Libido reticularis

● By inhibiting endonuclease
o No 5’-capped, 3’-polyadenylated
▪ No transcription
(i) Baloxavir
→ Utilized in influenza type A and B
→ <48 hours of symptoms onset
→ Reduces the severity of symptoms but doesn’t
prevents infection.
(iii) Prolong QT interval

→ Increased risk of Torsade de pointes
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(3) Neuraminidase Inhibitors

● By inhibiting NA
o Virus won’t be released from the epithelial cell to
infect other cells.
(i) Oseltamivir
(ii) Zanamivir
→ Utilized in influenza type A and B
→ Prophylaxis in
→ Adults
→ Kids >5 years old
→ <48 hours of symptoms onset
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III) HBV MEDICATIONS

(A) LIFE CYCLE
(1) Structure
(i) Unique features
● Has enveloped virion containing partially doubled-
stranded circular DNA genome
● Virus encodes and carries a reverse transcriptase.
● Encodes several proteins: HBsAg, HBe/HBc antigens.
● Strict tissue tropism to the liver.
(2) Replication
(i) Attachment to hepatocytes
(iii) Transcription
a. Mediated by the HBsAg glycoproteins.
a. Two different types of RNA:
i. mRNA
→ Uses host cells ribosomes to make different
types or proteins:
a. Structura proteins:
i. HBc and HBe antigens.
b. Functional proteins:
i. Polymerase and protein primer for
DNA replication.
ii. Pre-genomic RNA:
→ It gets converted into partially doubled-stranded
DNA by the action of the reverse transcriptase.
(ii) Penetration into the cell
a. Once into de hepatocyte the nucleocapsid delivers
the genome into the nucleus.
b. Partial DNA strand of the genome is completed to
form a complete double-stranded DNA circle.
→ It can start replication from here.
(B) DRUGS
(1) Reverse Transcriptase Inhibitors (2) IFN-alfa
● By inhibiting RT viral DNA won’t be produced
(i) Nucleoside Reverse Transcriptase Inhibitors

(NRTI’s)
→ Reverse transcriptase interacts with the NRTIs
terminating the formation of further DNA
(a) Lamivudine
(b) Entecavir
(ii) Nucleotide Reverse Transcriptase Inhibitors
(NtRTI’s)
→ Terminate the formation of DNA for their interaction
with RT as they don’t allow polymerization of the
genoma. → Its released by infected cells during a viral infection
→ Travel through bloodstream and binds to healthy cells
(a) Adefovir
to prevent them to get infected by stimulating proteins
(b) Tenofovir production:
1. Antiviral peptides
→ They inhibit viral proteins synthesis
→ Inhibit viral RNA production
2. Increase MHC-1 complex expression
→ Increase CD8+ T cells response to kill
infected cells
→ Can be used for HBV infection or refractory HCV
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(iii) Adverse effects of RT Inhibitors
(a) Fanconi Syndrome
→ Especially with Adefovir or tenofovir
→ Very rear
o Triad:
i. Phosphaturia (i) Adverse Effects & CI:
ii. Glycosuria
iii. Aminoaciduria (a) Teratogenic
(b) Pancytopenia
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IV) HEPATITIS C
● Hepatitis C attacks the liver cells → damage hepatocytes and ↑ risk of HCC.
LIFE CYCLE ANTI HCV DRUGS

● When HCV binds to hepatocytes, it uses many receptors. (1) PROTEASE INHIBITORS
● Since HCV is an RNA virus, when it binds to the cell and
enters the cell via endocytosis ● Directly acts on the NS3/4A protease → inhibits the
→ it uncoats inside the cell and release its RNA into the
cleavage of the poly protein and prevents formation of the
host cell cytoplasm. structural and functional proteins.
→ RNA then binds to ribosomes in the RER → the o Drugs: Simeprevir, Paritaprevir, Glecaprevir
ribosomes utilize the RNA to translate and
synthesize polyproteins.
(2) NS5A INHIBITORS
● NS5A is believed to act as an integral protein that is
Polyproteins that are produced are made up of needed for RNA replication.
these subunits: o It is also involved in the process of viral assembly
▪ NS3 where the protein products are transferred to the golgi
▪ NS4A apparatus.
▪ NS5A ● These drugs inhibits the NS5A which prevents RNA
▪ NS5B replication and viral assembly of HCV.
o Drugs: Ledipasvir, Velpatasvir, Daclatasvir
● The protease (NS3/4A protease) in the cytoplasm cleaves
the polyprotein between the NS3 and NS4A site to
produce: (3) NS5B INHIBITORS
→ Structural proteins (e.g. envelope proteins, etc)
→ Functional proteins (e.g. proteases, polymerases, etc) ● NS5B acts as an RNA dependent RNA polymerase so it
is used to make more RNA.
→ The drugs will prevent the formation of more HCV
These are important for the virus to replicate and infect
other cells. RNA
o Drugs: Sofosbuvir, Dasabuvir
● NS5A and NS5B are particular enzymes that are utilized

to be able to replicate and make more HCV RNA.
o Note: NS5A’s function is not fully known but NS5B is
definitely involved in this process.
There are drugs that target NS5A and NS5B in order to

inhibit the replication of the HCV RNA.
● All the products produced in this process; structural and

functional proteins and the RNA virus are transported to
the Golgi apparatus. Figure 2. NS5A and NS5B inhibitors preventing RNA replication
→ They are packaged to make a new virus.
→ Then the new virus is pushed out of the cell via
exocytosis to infect other cells.
When to know which one to use?

This is complicated and it depends on the genotype of
the HCV virus. There are many different genotypes and
each one determines which drug combination to use.
The most common combination is: Sofosbuvir

(NS5BI) and Ledipasvir (NS5AI).
Figure 1. Life Cycle of Hepatitis C
(5) RIBAVIRIN
● This is mostly used in refractory/resistant HCV and
depends on the particular type of genotype of the virus.
o This is a part of a triple therapy:
▪ Rubavirin + Sofosbuvir (NS5B) + Interferon alpha
● This combo inhibits a particular enzyme called Inosine 5-
phosphate Dehydrogenase (I5-P DH), this enzyme is
involved in the synthesis of guanine nucleotides.
o Guanine nucleotides are important for the synthesis of
more RNA. This is needed to be utilized by NS5A and
NS5B to add onto the RNA.
● Ribavirin inhibits I5-P DH enzyme → prevents formation
of guanine nucleotides → can’t be used to make RNA by
NS5A and NS5B.
→ Inhibits RNA replication and formation
Adverse Effects:
● Protease inhibitors, NS5AI and NS5BI are relatively well
tolerated.
o Be careful with patients with decompensated
cirrhosis
● Ribavirin is the only drug in this category that has severe

AE:
→ Teratogenic
→ ↑ risk of Hemolytic Anemia
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Figure 3. Mechanism of Action of Ribavirin
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II.HERPES VIRUS
The main herpes virus: Herpes Simplex Virus (HSV), Varicella Zoster Virus (VZV) and Cytomegalovirus (CMV)
These viruses attack specific tissues:

Virus Tissue Pathology LIFE CYCLE
Skin Mucocutaneous lesions by ● Herpes virus binds to the receptors and get taken into the
HSV-1 and HSV-2
cell via endocytosis → undergoes uncoating and release
HSV Esophagus HSV esophagitis
DNA into the host cell → the virus’ DNA and DNA
Meninges in HSV encephalitis meningitis polymerases enter the nucleus.
brain tissue
Nerves stays dormant in nerves and The herpes virus replicates by using both DNA polymerase
VZV manifest as shingles when and RNA polymerase.
activated
Esophagus Esophagitis o In the nucleus, a viral DNA polymerase will
CMV Lungs Pneumonia stimulate formation of viral DNA → the DNA is
Retina CMV retinitis pushed into the cytoplasm and sent to the golgi
apparatus
▪ The nucleic acid of the DNA is incorporated with
the other components formed by the mRNA →
virus is formed.
o RNA polymerase of the viral DNA can also produce

mRNA → mRNA leaves the nucleus and enters the
ribosomes → ribosomes use the mRNA to synthesize
the proteins integral to making the herpes viruses
(e.g. structural proteins, functional proteins, etc.)
Figure 4. Target organs of Herpes Virus ▪ The proteins made are sent to the golgi apparatus
→ they then combine with the nucleic acid via
viral assembly
→ The virus is then packaged in a vesicle →
the vesicle fuses with the cell membrane and
releases the virus via exocytosis.
c
Figure 5. Life cycle of Herpes Virus
ANTI HERPES DRUGS
● The most important target of these drugs is the process of formation of new viral DNA because this prevents both:
o Replication of viral DNA
o Formation of mRNA
VIRAL DNA POLYMERASE INHIBITORS GUANOSINE ANALOGS

● This targets the DNA polymerase → inhibits viral DNA ● The drug is taken up into the cell and processed by the
replication and mRNA formation → therefore there is ↓ viral kinase enzyme
mRNA → ↓ proteins → ↓ less viral assembly → ↓ new
viruses. Viral Kinase Enzymes:
o Drugs: Cidofovir, Foscarnet o Thymadine acts on acyclovir and valacyclovir
o UL97 kinase acts on the Gancyclovir
REMEMBER:
● Cidofovir acts directly by binding on the the DNA ● The viral kinase enzyme adds on many phosphate groups
polymerase and inhibiting it. onto the guanosine analog drugs to form a structure that
● Foscarnet acts like a pyrophosphate analog that looks like a nucleotide
inhibits DNA polymerase. o Now, during the process of viral replication, the DNA
polymerase will utilize the “fake” nucleotide /
guanosine analog.
Indications: → This will terminate DNA and RNA formation as
the DNA polymerase will be unable to add on
● CMV infections (especially those resistant to Gancylcovir)
more nucleotides to the DNA strand.
● Acyclovir resistant HSV infections
o Mains drugs: Acyclovir, Valacyclovir, Gancyclovir
Adverse Effects:
Indications:
● Cidofovir:
● Acyclovir, Valacyclovir for HSV (mucocutaneous
o Crystal Induced Nephropathy (can lead to acute
lesions and esophagitis) and VZV infections (shingles).
kidney injury)
● Gancyclovir for CMV infections.
▪ Administer with IV fluids and probenecid (can ↓
nephropathy).
Adverse Effects:
● Foscarnet: ● Nephrotoxicity (very specific to acyclovir)
o Increases risk of seizures o Administer with many IV fluids to reduce the risk
▪ This drug produces massive electrolyte
imbalances, alterations in (↓/↑) calcium, (↓/↑) ● Acyclovir and Valacyclovir: ↑ TTP (mechanism is
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phosphate, (↓) potassium and (↓) magnesium
which can potentially precipitate seizures.
unknown)
● Pancytopenia due to bone marrow suppression
(especially Gancyclovir)
Figure 7. Drugs and Adverse Effects of Guanosine Analog
Figure 6. MoA and Adverse Effects of Viral DNA polymerase

Inhibitors
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V) SUMMARY
Class Mechanism Adverse reactions Drugs Notes

● Enfuvirtide HAART (Highly
Fusion/entry Inhibits entry of the viral RNA into the host cell by ● Maraviroc active antiretroviral
● Inhibiting GP41 binding to CD4 (Enfuvirtide)
inhibitor ● Inhibiting GP120 binding to CCR5 (Maraviroc)
therapy)
● 2 NRTI’s + NNRTI’s
Mitochondrial toxicity ● Zidovudine ● 2 NRTI’s + Integrase
● Inhibit the reverse transcriptase from taking RNA and making DNA by ● Myopathy ● Abacavir inhibitor
stopping the growing DNA template ● Peripheral neuropathy ● Lamivudine ● 2 NRTI’s + Protease
o By acting like a nucleotide even though it’s not ● Hepatic steatosis ● Emtricitabine inhibitor
o It will terminate the actual formation of DNA off of this RNA template ● Lactic acidosis ● Stavudine
NRTI strain Adjuvant therapy
(ZALES TD) Others ● Tenofovir ● Enfuvirtide
● Pancreatitis ● Didanosine ● Maraviroc
● Nephrotoxicity
● Bone marrow suppression
● Hypersensitivity reaction
● Nevirapine
● Allosteric inhibitors ● Hepatotoxicity ● Efavirenz
HIV
NNRTI (-vir) ● Binds onto a particular site ● CNS toxicity ● Etravirine

o Inhibiting the reverse transcriptase enzyme from being able to ● Teratogenic effect ● Delavirdine
properly function and taking RNA and making DNA
Integrase ● Rhabdomyolysis ● Dolutegravir

● Not allowing for the actual viral DNA to be incorporated into the host cell ● Raltegravir
Inhibitor DNA ● Elvitegravir
(-gravir)
● Crystal-induced ● Atazanavir
● Inhibit protease → won’t be able to cleave the polyproteins that were nephropathy ● Darunavir
translated ● Lipodystrophy ● Indinavir
o They won’t be able to make any structural and functional proteins ● CYP450 inhibitor ● Lopinavir
Protease o They won’t have ● Nelfinavir
inhibitor ▪ Core proteins ● Saquinavir
▪ Capsular proteins ● Tipranavir
(-navir) ▪ Enzymes inside the virus ● Ritonavir
▪ GP proteins on the surface
● Can’t make new virus
● It inhibits uncoating and doesn’t allow viral ARN go ● Ataxia ● Amantadine ● Amantadine is the
● Uncoating into the cytoplasm ● Libido reticularis only one that tends
inhibitor ● Prolonged QT interval to cause adverse
reactions.
● By inhibiting endonuclease there won’t be 5’- ● Baloxavir

INFLUENZA ● Endonuclease capped,3’-polyadenylated
inhibitor ● Inhibits transcription
● NA doesn’t release virus from the epithelial cell to ● Oseltamivir

● Neuraminidase infect other cells ● Zanamivir
inhibitor
● NRTI’s ● Reverse transcriptase interacts with the NRTIs, ● Fanconi Syndrome ● Lamivudine
terminating the formation of further DNA. ● Phosphaturia ● Entecavir
● Glycosuria
RTI
● Aminoaciduria
● NtRTI’s ● Terminate the formation of DNA for their interaction ● Adefovir

with RT as they don’t allow polymerization of the ● Tenofovir
genoma.
HBV
● ● Stimulates production of ● Teratogenic
● IFN-alfa antiviral peptides ● Pancytopenia
● Decrease of protein
synthesis
● Decrease of viral RNA
● Stimulates expression of
MHC type I
● Directly acts on the NS3/4A protease → inhibits the These are relatively well
● Protease cleavage of the poly protein and prevents tolerated. ● Simeprevir
Inhibitors formation of the structural and functional proteins. Be careful with patients with ● Paritaprevir
decompensated cirrhosis. ● Glecaprevir
● Inhibits the NS5A which prevents RNA replication ● Ledipasvir

● NS5A and viral assembly of HCV. ● Velpatasvir
Inhibitors ● Daclatasvir
● NS5B acts as an RNA dependent RNA polymerase ● Sofosbuvir

● NS5B ● Dasabuvir
HCV Inhibitors
so it is used to make more RNA. The drugs will
prevent the formation of more HCV RNA.
● Ribavirin inhibits the I5-P DH enzyme ● Ribavirin ● This is part of a

● Ribavirin → prevents formation of guanine nucleotides ● Teratogenic triple therapy and it
→ can’t be used to make RNA by NS5A and ● ↑ risk of Hemolytic Anemia is mostly used in
NS5B refractory/resistant
→ inhibits RNA replication and formation. HCV and depends
on the particular
type of genotype of
the virus.
● This targets the DNA polymerase ● Cidofovir,

● Viral DNA → inhibits viral DNA replication and mRNA ● Cidofovir → ● Foscarnet
polymerase formation. crystal induced
Inhibitors nephropathy (can lead to
● Therefore, there is ↓ mRNA acute kidney injury)
→ ↓ proteins
→ ↓ less viral assembly ● Foscarnet →
→ ↓ new viruses. Increases risk of seizure
HSV ● The viral kinase enzyme adds on many phosphate ● Acyclovir → ● Acyclovir
● Guanosine groups onto the guanosine analog drugs to form a Nephrotoxicity ● Valacyclovir
Analogs structure that looks like a nucleotide. ● Gancyclovir
o Now, during the process of viral replication, ● Acyclovir and Valacyclovir
the DNA polymerase will utilize the → ↑ TTP
guanosine analog.
● Gancyclovir →
● This will terminate DNA and RNA formation as the Pancytopenia
DNA polymerase will be unable to add on more
nucleotides to the DNA strand.
VI) REVIEW QUESTIONS VII) REFERENCES
1) Maraviroc can be given in any patients because all T
helper cells express CCR5 in all patient population
a) True
b) False
2) NRTI is known to cause mitochondrial toxicity, which
below are the side effects that can be found due to
mitochondrial toxicity, EXCEPT?
a) Myopathy
b) Lactic acidosis
c) Hepatic steatosis
d) Pancreatitis
3) Which of the following antivirals used in influenza
inhibits NA interfering with its release from infected
epithelial cells?
a) Amantadine
b) Baloxavir
c) Zanamivir
d) Lamivudine
4) Select the correct adverse effect that can be seen
when using amantadine:
a) Phosphaturia
b) Aphasia
c) Arrythmias
d) Prolonged QT interval
5) True or false? IFN-a can be produced naturally by
infected cells or can be administered as therapy:
a) True
b) False
6) Which of the following drugs directly acts on the
NS3/4A protease and inhibits the cleavage of the
polyprotein formed by HCV?
a) Daclatasvir
b) Ribavirin
c) Paritaprevir AfraTafreeh.com
d) Dasabuvir
7) Which of the following drugs inhibits the enzyme
Inosine 5-phosphate Dehydrogenase that prevents
the formation of guanine nucleotides?
a) Ribavirin
b) Gancyclovir
c) Ledipasvir
d) Cidofovir
8) What is the main adverse effect of Cidofovir?
a) Seizures
b) Crystal Induced Nephropathy
c) Hemolytic Anemia
d) Teratogenic
9) Which drug is most commonly used for CMV
infections?
a) Gancyclovir
b) Acyclovir
c) Foscarnet
d) Dasabuvir

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6. ANTIVIRALS | HIV, HEPATITIS, INFLUENZA, HERPES TREATMENT

I) ANTIRETROVIRAL THERAPIES - HIV TREATMENT

(A) VIRAL FUSION - FUSION/ENTRY INHIBITOR

(i) Drugs (i) Drugs

Mnemonics: ZALES TD AfraTafreeh.com

(D) VIRAL POLYPEPTIE PROCESSING - PROTEASE INHIBITOR

(i) Drugs Polypeptide processing by protease

(F) HIGLY ACTIVE ANTIRETROVIRAL THERAPY (HAART REGIMENT)

Adjunct therapy (ii) Enfuvirtide

the HIV genotype

ADVERSE EFFECTS AND CONTRAINDICATIONS

• Backbone of the HAART (highly active antiretroviral therapy)

(1) Rhabdomyolysis & myoglobin in the urine

II) INFLUENZA MEDICATIONS

(iii) Membrane protein (M2)

(iv) Matrix protein (M1)

(v) Nucleocaspid protein (NP)

(2) Replication (v) Replication

(2) Endonuclease Inhibitor (ii) Libido reticularis

(iii) Prolong QT interval

(3) Neuraminidase Inhibitors

III) HBV MEDICATIONS

(i) Nucleoside Reverse Transcriptase Inhibitors

LIFE CYCLE ANTI HCV DRUGS

● NS5A and NS5B are particular enzymes that are utilized

There are drugs that target NS5A and NS5B in order to

● All the products produced in this process; structural and

When to know which one to use?

The most common combination is: Sofosbuvir

Figure 1. Life Cycle of Hepatitis C

● Ribavirin is the only drug in this category that has severe

Figure 3. Mechanism of Action of Ribavirin

These viruses attack specific tissues:

o RNA polymerase of the viral DNA can also produce

VIRAL DNA POLYMERASE INHIBITORS GUANOSINE ANALOGS

Figure 7. Drugs and Adverse Effects of Guanosine Analog

Figure 6. MoA and Adverse Effects of Viral DNA polymerase

Class Mechanism Adverse reactions Drugs Notes

NNRTI (-vir) ● Binds onto a particular site ● CNS toxicity ● Etravirine

Integrase ● Rhabdomyolysis ● Dolutegravir

● By inhibiting endonuclease there won’t be 5’- ● Baloxavir

● NA doesn’t release virus from the epithelial cell to ● Oseltamivir

● NtRTI’s ● Terminate the formation of DNA for their interaction ● Adefovir

● Inhibits the NS5A which prevents RNA replication ● Ledipasvir

● NS5B acts as an RNA dependent RNA polymerase ● Sofosbuvir

● Ribavirin inhibits the I5-P DH enzyme ● Ribavirin ● This is part of a

● This targets the DNA polymerase ● Cidofovir,

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