Antiviral Chemotherapy

Viruses
• Obligate intracellular parasites
• Consist of a core genome in a protein shell and some
are surrounded by a lipoprotein
• lack a cell wall and cell membrane
• do not carry out metabolic processes
• Replication depends on the host cell machinery
 Viruses
• Steps for Viral Replication
1. adsorption and penetration into cell
2. uncoating of viral nucleic acid
3. synthesis of regulatory proteins
4. synthesis of RNA or DNA
5. synthesis of structural proteins
6. assembly of viral particles
7. release from host cell
 Antiviral agents
• Exert their actions at several stages of viral replication
process
• Most are active against herpes viruses (HSV), human
immunodeficiency virus (HIV)
• The selective toxicity of antiviral drugs usually depends
on greater susceptibility of viral enzymes to their
inhibitory actions than host cell enzymes.
Sites of Drug Action
 Antiviral Agents

• Block viral entry into the cell or must work

inside the cell
• Most agents are pyrimidine or purine
nucleoside analogs
Sites of Drug Action
 Antiherpes Agents

• Acyclovir- prototype
• Valacyclovir
• Famciclovir
• Penciclovir
• Docosanol
• Trifluridine
• Vidarabine
 Mechanism of Action Acyclovir
• an acyclic guanosine derivative
• Phosphorylated by viral thymidine kinase
• Di-and tri-phosphorylated by host cellular enzymes
• Inhibits viral DNA synthesis by:
1) competing with dGTP for viral DNA polymerase
2) chain termination
Mechanism of Resistance Acyclovir

• Alteration in viral thymidine kinase

• Alteration in viral DNA polymerase

• Cross-resistance with valacyclovir, famciclovir, and

ganciclovir
 Pharmacokinetics
Acyclovir
• Oral, IV, and Topical formulations
• diffuses into most tissues and body fluids to produce
concentrations that are 50-100% of those in serum. e.g.
CSF
• Cleared by glomerular filtration and tubular secretion
 Clinical Uses
Acyclovir
• Uses:
– Herpes Simplex Virus 1 and 2 (HSV)
• Oral acyclovir is effective for treatment of primary
infection and recurrences of genital and labial herpes.
• Intravenous acyclovir is the treatment of choice
for herpes simplex encephalitis, neonatal HSV
infection and
• for severe primary, recurrent HSV genital and
labial infections and for those who cannot ingest
oral pills
– Varicella-zoster virus (VZV)
 Clinical Uses
Acyclovir
• Side Effects
– Depends on the route of adm.
• IV= renal dysfunction, neurotoxicity (tremors, and delirium)
• Oral = diarrhea and headache
• Topical = local irritation
 Valacyclovir
• L-valyl ester of acyclovir
• Converted to acyclovir when ingested
• 3-5 x < Cp than Acyclovir
• M.O.A.: same as acyclovir
• Uses:
– 1) recurrent genital herpes
– 2) herpes zoster infections
• Side Effects: nausea, diarrhea, and headache
 Famciclovir
• Prodrug of penciclovir (an acyclic guanosine analog)
• M.O.A.: same as acyclovir
– does not cause chain termination
• Uses: HSV-1, HSV-2, VZV, EBV, and hepatitis B
– Effective in tt of first and recurrent genital herpus, and for
acute zoster
• Side Effects: nausea, diarrhea, and headache
 Penciclobir
• Guanosine anolog, active metabolite of famciclovir
• Available for topical use
• For recurrent Herpes labialis in immunocompetent
adults
• Side effects are uncommon
 Trifluridine

• Trifluridine- fluorinated pyrimidine

– inhibits viral DNA synthesis same as acyclovir
– Phosphorelated by host cell enzymes
– incorporates into viral and host DNA
• Prevents it’s systemic use
• Uses: HSV-1 and HSV-2 (topically)
 Docosanol
• A saturated aliphatic alchol
• Inhibits fusion b/n the plasma membrane and
the HSV envelop
– Prevent viral entry
• Topical cream
 Vidarabine
• An adenosine analog
• Inhibits viral DNA polymerase
• Incorporated into viral and cellular DNA
• Metabolized to hypoxanthine arabinoside
• Side Effects: GI intolerance and myelosuppression
• active against HSV-1, HSV-2, and VZV,
• But, use limited to immunocompromised patients with
herpetic and vaccinial keratitis and in HSV
keratoconjunctivitis.
 Anti-Cytomegalovirus Agents

• Gancyclovir
• Valgancyclovir
• Cidofovir
• Foscarnet
 Ganciclovir

• An acyclic guanosine analog

• requires triphosphorylation for activation
• monophosphorylation is catalyzed by a
phosphotransferase in CMV and by thymidine kinase in
HSV cells
• M.O.A.: same as acyclovir
• Po, IV, Intraocular implant
• Uses: CMV* (100x Acyclovir), HSV, VZV,and EBV
• Side Effect: myelosuppression (neutropenia).
 Valgancyclovir
• L-valyl ester prodrug of gancyclovir
• Metabolized by intestinal and hepatic esterases
when administered orally
• Recommended to be taken with food
• M.O.A.: same as gancyclovir
• Uses: CMV*
• Side Effect: myelosuppression
 Cidofovir
• A cytosine analog
• phosphorylation not dependent on viral enzymes
• Uses: CMV*, HSV-1, HSV-2, VZV, EBV, HHV-6, adenovirus,
and human papillomavirus
• Side Effects: nephrotoxicity (IV must be admin. w/
probenecid)
• Resistance: mutation in DNA polymerase gene
 Foscarnet
• An inorganic pyrophosphate
• inhibits viral DNA polymerase, RNA polymerase, and HIV
reverse transcriptase
• without requiring phosphorylation.
• Uses: HSV, VZV, CMV, EBV, HHV-6, HBV, and HIV
• Foscarnet is used for patients with CMV retinitis and
acyclovir-resistant HSV infection
• Foscarnet has also been used to treat CMV colitis and
esophagitis and acyclovirresistant VZV infection.
 Foscarnet
• Resistance due to mutations in DNA polymerase gene
• IV only; Poor oral BA and GI intolrance
• Side Effects: renal insufficiency, hypocalcemia or
hypercalcemia, and hypo-or hyperphosphatemia
– Genital ulcerations associated with foscarnet therapy
may be due to high levels of ionized drug in the urine.
– Central nervous system toxicities include
hallucinations, and seizures.
 Fomivirsen
• an antisense oligonucleotide
• M.O.A.: binds to mRNA and inhibits protein synthesis
and viral replication
• Uses: CMV retinitis (for those who cannot
tolerate/failed
• IV
• Side effects: iritis and increased intraocular pressure,
change in vision
 Antiretroviral Agents
1) Nucleoside Reverse Transcriptase Inhibitors
(NRTIs)
2) Nonnucleoside Reverse Transcriptase
Inhibitors (NNRTIs)
3) Protease inhibitors
4) Entry inhibitors
5) Integrase inhibitors
 Classification
1. Reverse Transcriptase Inhibitors

A. Nucleoside/Nucleotide Reverse Transcriptase Inhibitors

(NRTIs/NtRTIs)
Zidovudine (ZDV)*
Didanosine (ddi)*
Lamivudine (3TC)*
Zalcitabine (ddC)
Stavudine (d4T)*
Abacavir (ABC)*
Emtricitabine (FTC)
Tenofovir disoproxil fumarate(TDF) :NtRI
 Classification (cont.)
B. Non-Nucleoside Reverse Transcriptase Inhibitors
(NNRTIs)
Nevirapine (NVP)*
Delavirdine (DLV)
Efavirenz (EFV)*
 Classification Cont.
2. Protease Inhibitors (PIs)
Saquinavir (SQV)*
Ritonavir (RTV)*
Indinavir (IDV)*
Nelfinavir (NFV)*
Amprenavir (APV)
Fos-amprenavir (f-APV)
Lopenavir/ritonavir (LPV/r)*
Atazanavir (ATZ)
3. Fusion inhibitors
Enfuvirtide (T-20)
 Reverse Transcriptase Inhibitors

• Zidovudine (AZT)
• Didanosine- causes pancreatitis*
• Lamivudine- causes pancreatitis
• Zalcitabine- causes peripheral neuropathy*
• Stavudine- causes peripheral neuropathy*
• Abacavir
 Chemistry of NRTIS
NRTI Nucleoside/ Nucleotide base
Zidovudine thymine
Didanosine adenine
Lamivudine cytosine
Zalcitabine cytosine
Stavudine thymine
Abacavir guanine
Emtricitabine cytosine
*Tenofovir disoproxil adenine
fumarate
* Adenine mono phosphate
Mechanism of action

IC kinase
Drug drug-triphosphate

Cellular
triphosphates X  pro-viral DNA
Reverse
Transcriptase 
viral
replication

N.B. HIV reverse transcriptase is 20-30 times

more susceptible than alpha DNA
polymerase of the mammalian cells, but
gamma DNA polymerase is equally
susceptible
 Mechanism of Action
Zidovudine (AZT)
• A deoxythymidine analog
• enters the cell via passive diffusion
• must be converted to the triphosphate form by
mammalian thymidine kinase
• competitively inhibits deoxythymidine triphosphate
for the reverse transcriptase enzyme
• causes chain termination
 Mechanism of Resistance
Zidovudine

• Due to mutations in the reverse transcriptase

gene

• more frequent after prolong therapy and in

persons with HIV
 Clinical Uses
Zidovudine
• Available in IV and oral formulations
• activity against HIV-1, HIV-2, and human T cell
lymphotropic viruses
• mainly used for treatment of HIV, decreases
rate of progression and prolongs survival
• prevents mother to newborn transmission of
HIV
 Side Effects
Zidovudine
• Myelosuppression, including anemia and
neutropenia

• GI intolerance, headaches, and insomnia

 Other NRTIs
• Didanosine (ddI)- synthetic deoxy-adenosine analog; food
reduces BA, causes pancreatitis*
• Lamivudine(3TC)- cytosine analog
• Zalcitabine(ddC)- cytosine analog; causes peripheral
neuropathy*
• Stavudine(d4T)- thymidine analog;causes peripheral
neuropathy*
• Abacavir(ABC)- guanosine analog; more effective than the
other agents; fatal hypersensitivity reactions can occur
 Nucleotide Inhibitors
Tenofovir (TDF)
• An acyclic nucleoside phosphonate analog of
adenosine
• M.O.A.- competively inhibits HIV reverse
transcriptase and causes chain termination after
incorporation into DNA
• Uses – in combination with other antiretrovirals for
HIV-1 suppression
 Nonnucleoside Reverse Transcriptase
Inhibitors (NNRTIs)

• Nevirapine (NVP)
• Delavirdine (DLV)
• Efavirenz (EFV)
 Mechanism of Action
NNRTIs
• Bind to site on viral reverse transcriptase, different
from NRTIs
– results in blockade of RNA and DNA dependent DNA
polymerase activity
– do not compete with nucleoside triphosphates
– do not require phosphorylation
• these drugs can not be given alone
• substrates and inhibitors of CYP3A4
 Nonnucleoside Reverse Transcriptase
Inhibitors (NNRTIs)
• Nevirapine- prevents transmission of HIV from
mother to newborn when given at onset of labor and
to the neonate at delivery
• Delavirdine- teratogenic, therefore can not be given
during pregnancy
• Efavirenz- teratogenic, therefore can not be given
during pregnancy
 Protease Inhibitors
• Indinavir (IDV)
• Ritonavir (RTV)
• Saquinavir (SQV)
• Nelfinavir (NFV)
• Lopenavir (LPVr)
• Atazanavir (ATV)
 Protease Inhibitors
• The protease enzyme cleaves precursor molecules to
produce mature, infectious virions
• inhibit protease and prevent the spread of infection
• cause a syndrome of altered body fat distribution,
insulin resistance, and hyperlipidemia
 Indinavir and Ritonavir
• M.O.A.: Specific inhibitors of the HIV-1 protease enzyme
• M.O.R.: mediated by expression of multiple and variable
protease amino acid substitutions
• Side Effects: hyperbilirubinemia
• Contraindications:inhibitor/substrate for CPY3A4, do not
give with antifungal azoles
 Saquinavir
• A synthetic peptide-like substrate analog

• inhibits HIV-1 protease

• prevents cleavage of viral polyproteins

 Nelfinavir and Amprenavir

• M.O.A.: Specific inhibitors of the HIV-1 protease

enzyme
• M.O.R.: mediated by expression of multiple and
variable protease amino acid substitutions
• Less cross-resistance with Amprenavir
• Side Effects: diarrhea and flatulence
• Amprenavir can cause Stevens-Johnson syndrome
• Contraindications:inhibitor/substrate for CPY3A4
 Fusion Inhibitors
• Enfuvirtide (T-20)- binds to the gp41 subunit of the
viral envelope glycoprotein, preventing the
conformational changes required for fusion of the
viral and cellular membranes
• By blocking fusion (entry into cell), prevents HIV from
infecting CD4 cells
• NRTI, NNRTI & PI classes prevent the replication of HIV by working inside
CD4 cells after they have been infected with HIV.

• The drugs in these three classes then target specific steps in the replication
process to prevent the creation of new HIV particles.

• Fusion inhibitors differ from these drugs because they work on the outside
of the cell to prevent HIV from fusing with, and infecting the CD4 cells in
the first place.
 Anti-Hepatitis Agents
• Lamivudine -Nucleoside Reverse Transcriptase
Inhibitor (NRTI)
• Adefovir -Nucleotide Inhibitor
• Interferon Alfa
• Pegylated Interferon Alfa
• Ribavirin
 Interferons
Interferon Alfa
• Endogenous proteins
• induce host cell enzymes that inhibit viral RNA
translation and cause degradation of viral mRNA and
tRNA
• Bind to membrane receptors on cell surface
• May also inhibit viral penetration, uncoating, mRNA
synthesis, and translation, and virion assembly and
release
 Interferons
• Pegylated interferon Alfa
• A linear or branced polyethylene gylcol (PEG)
moiety is attached to covalently to interferon
• Increased half-life and steady drug
concentrations
• Less frequent dosing
• Tx chronic hepatitis C in combination with
ribavirin
 Ribavirin
• A guanosine analog
• phosphorylated intracellularly by host
enzymes
• inhibits capping of viral messenger RNA
• inhibits the viral RNA-dependent RNA
polymerase
• inhibits replication of DNA and RNA viruses
 Anti-Influenza Agents
• Amantadine
• Rimantadine
• Zanamivir
 Amantadine and Rimantadine

Amantadine Rimantadine
– cyclic amines
– inhibit the uncoating of viral RNA therefore inhibiting
replication
– resistance due to mutations in the RNA sequence
coding for the structural M2 protein
– used in the prevention and treatment of Influenza A
 Zanamivir and Oseltamivir

• Inhibits the enzyme neuraminidase

• inhibit the replication of influenza A and Influenza
B
– and are currently active against both H3N2 and H1N1
strains
• treats uncomplicated influenza infections
• administered intranasally