Antiviral Agents

• Restricted spectrum
• No standardized in-vitro susceptibility tests
• Most inhibit replication. Cure depends on host
immune system to eradicate. If patients are
immunocompromized, may have recurrences.
• Many need to be activated by viral and cellular
enzymes before exerting antiviral effect. Activity
of enzymes and concentration of substrates will
influence the efficacy.
 Classification
• Purine and Pyrimidine Analogues (Herpes, CMV,
HIV, Resp. Syncitial)
• Non-nucleoside inhibitors of reverse transcriptase
(HIV)
• Direct inhibitor of DNA polymerase and RT –
Foscarnet
• Protease Inhibitors (HIV)
• Interferon-alpha (Hep. B&C, Herpes)
• Others: Amantadine, Rimantadine (Influenza)
 Nucleoside Analogues
General Mechanism of Action
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1. Taken up by cells
2. Converted by viral and cellualr enzymes to the
triphosphate form
3. The triphosphate form inhibits:
• DNA polymerase
• Reverse transcriptase
• RNA polymerase
• Or it may get incorporated into growing DNA
leading to abnormal proteins or breakage.
 Acyclovir
and Valacyclovir (prodrug, better availability)
A Guanine analogue with antiviral for Herpes group only
Acyclovir AcycloGMP AcycloGTP
Thymidine kinase Cellular kinases
Viral 200x affinity
of mammalian

1. Inhibits viral DNA polymerase selectively

2. Incorporated into DNA and terminates synthesis
Resistance: Toxicity: Use:
1. ↓ activity of thymidine kinase 1. Encephalopathy 1. H. simplez I and II
2. altered DNA polymerase 2. Renal Insuficiency 2. H. zoster and Varicella,
not good for CMV
 Ganciclovir
• Mechanism like Acyclovir
• Active against all Herpes viruses including CMV
• Low oral bioavailability given I.V.
• Most common adverse effect: bone marrow
suppression (leukopenia 40%, thrombocytopenia
(20%) and CNS effects (headache, behavioral,
psychosis, coma, ocnvulsions).
• 1/3 of patients have to stop because of adverse
effects
• Drug of choice for CMV infections: retinitis,
pneumonia, colitis…
Acyclovir Ganciclovir

Guanine
 Other Nucleoside Analogues
Vidarabine
• Poor solubility, give i.v. with
big volume of fluids (2.5 L)
⇒ risk of fluid overload
• Toxicity: GI; Bone marrow;
Hypokalemia; inappropriate
ADH secretion; (psychosis;
painful neuropathy;
• Not a drug of choice for
anything. Replaced by
Acyclovir because of toxicity
and problems in
administration.
Idoxuridine and
Trifluridine
• Topical agents for Herpes keratitis
• Trifluridine also for CMV and
others
• Trifluridine better for H. simplex II
keratoconjuctivitis
Ribavirin
• Aerosol: inhibits replication of
Influenza A & B and RCV
• Triphosphate inhibits RNA
polymerase
• Anemia due to hemolysis and BM
suppression
 Foscarnet
• An inorganic pyrophosphate analog
• Active against Herpes (I, II, Varicella , CMV),
inlcuding those resistant to Acyclovir and Ganciclovir.
• Direct inhibition of DNA polymerase and RT
• Nephrotoxicity (25%) most common ADR
• Hypocalcemia (chelates divalent cations)
• Others: hypokalemia, hypomagnesemia
• Use: CMV retinitis and other CMV infections instead
of ganciclovir. H simplex resistant to Acyclovir. HIV.
 Anti-retroviral Agents
• Zidovudine (AZT)
• Cellular enzyme phosphorylate to the triphosphate form
which inhibits RT and causes chain termination
• Adverse effect:
– Granulocytopenia and anemia: 45% in AIDS but 5% if
asymptomatic HIV
– Severe headache, nausea, insomnia, myalgias
• ↓mortality & opportunistic infections, gain weight, better
quality of life, delays signs and symptoms of AIDS
Other Retroviral RT Inhibitors
• Other nucleoside analogs: didanosine, stavudine,
zalcitabine: same as AZT but can cause peripheral
neuropathy and pancreatitis. Can be used with
AZT for enhanced effect and less toxicity.
• Non-nucleoside RT inhibitors: e.g. neviparine.
Noncompetitive binding to RT and direct
inhibition at a site different from AZT and others.
May be active against AZT-resistant strains. Can
be used in combination. Main adverse effect is
rash (75).
 Protease Inhibitors
• Produce non-infectious particles or virions
• Reduces the number of new rounds of infection in
susceptible cells
• To be effective must be prolonged, profound and
constant.
• Pharmacokinetics important to maintain constant
concentrations within the effective range.
• Metabqolic adverse effects (DM, hyperglycemia)
and GI (diarrhea, pain vomiting).
 Protease Inhibitors

Protease action

Panel C shows the translational products of the HIV gag–pol gene and the sites
at which the gene product is cleaved by the virus-encoded protease. p17
denotes capsid protein, p24 matrix protein, and p7 nucleocapsid; p2, p1, and
p6 are small proteins with unknown functions. The arrows denote cleavage
events catalyzed by the HIV-specific protease.
Fig. 3. HIV-1 virion forms. (a) Particles assembling and budding at the cell
membrane. (b) An immature virus particle. (c) Mature forms of HIV-1.
 Other Drugs
Amantadine
• Prevents uncoating (?) &/or
assembly
• CNS Toxicity due to
dopaminergic action
• Prophylaxis of Influenza A
during epidemics.
• If used within 48 hours may
help cure Influenza infection
• Rimantadine: analog with
less CNS toxicity
Interferons
• Antiviral, anticancer and
immunomodulating
• Several sites of action in
viral cycle but mainly
inhibit translation of viral
proteins
• Toxicity: flu-like syndrome,
BM suppression; CNS
• Hepatitis B and C