Antiviral Agents

Introduction to Virus

Virus Structure

Surrounded by protein coat: Capsid

Contain crucial virus-specific enzymes

Nucleic acid core: DNA/RNA//S.S/D.S

Extremely genetic simplified (replication depends on host cell machinery)

No Metabolic processes are carried out

Has envelope (outer lipid layer which carries signaling molecules detected by cell surface receptor)

Small in size

Methods Used to combat viral infection

Prevention - Vaccines

Strengthen - Immunomodulators

Treatment - Antivirals

General approaches of Antiviral Treatments

Inhibitors of Viral Uncoating/Release: Anti-Influenze Agents

Block attachment

Block Penetration

Block uncoating

Inhibit transcription

Inhibit translation

Inhibit viral release

Inhibit viral assembly

Inhibit viral DNA/RNA synthesis

Inhibit specific viral enzymes

Inhibit viral protein synthesis

Amantadine (Viral uncoating inhibitor)

Rimantadine (Viral uncoating inhibitor)

Zanamivir (Relenza) (Neuraminidase inhibitor)

Oseltamivir (Tamiflu) (Neuraminidase inhibitor)

3 types of Influenza Virus

Subtypes defined by different antigens

A (more common), B and C

Subtypes of virus A

H (haemaglutinin)

N (Neuraminidase)

H3N2 (common human)

H7N7 (avian 2003)

H5N2 (avian)

H5N1 (current avian/human)

H1N1 (swine flu)

Inhibitors of Viral Uncoating

Amantadine & Rimantadine

Spectrum of Activity: Active against influenza A

MOA: Blocks M2 influenza A membrane protein (M2 protein acts as ion channel in endosome to mediate the uncoating process)

Inhibition of viral uncoating & assembly & release of virions at cell surface blocked

MOR: mutation of M2 protein, widespread circulation of resistant H3N2, H1N1, H5N1, cross-resistance with each other

Pharmacokinetics (ADME)

Mode of administration: Oral, inhalation

Well absorbed orally, crosses BBB

Amantadine levels in nasal secretion & saliva = in plasma

Rimantadine levels in nasal mucous 50% > in plasma

T1/2 (half-life): Amantadine = 12-18 hours ; Rimantadine = 24-36 hours

Majority of Amantadine excreted in URINE (unchanged) ; Majority of RImantadine excreted in URINE (metabolites)

Adverse effect

Dizziness (Amantadine)

Nervousness, insomnia, slurred speech

Nausea, loss of appetite

CNS side effects, less with rimantadine inhalation

Inhibitors of Viral Release

Oseltamivir & Zanamivir

Spectrum of Activity

MOA

MOR

Pharmacokinetics (ADME)

Adverse Effects

Active against influenza A & B (treatment & prevention)

Inhibit neuraminidase (required for viral release)

Natural resistance seems rare

Most oseltamivir-resistant viruses remain susceptible to zanamivir

Oseltamivir

Zanamivir

Oral absorption rapid, bioavailability 80%

Oral absorption NOT affected by food

Metabolised by esterases in GI tract & liver

T1/2: Oseltamivir carboxylate = 6-10 hours

Excreted via kidney

Low oral bioavailability (~2%), given via NASAL route

Not metabolized

Excreted UNCHANGED via kidneys

N/V/Abdominal discomfort

Headache

Food improves GI tolerance

Neuraminidase (NA)

An enzyme involved in various aspects of activation of influenza viruses

Involved in catalytically cleaving glycosidic bonds btwn a terminal sialic acid * an adj. sugar on hemaglutinin (HA) when the virus is budding off

This cleavage facilitates the release of viruses

Absence of this cleavage, viral binding to HA will occur

Viruses failed to be released from host cell & will aggregate at host cell surface

Anti-Herpes Agents

Aciclovir (Zovirax)

Valaciclovir (Valtrex)

Famciclovir

Penciclovir

Ganciclovir (Cymevene)

Valganciclovir (Valcyte)

Foscarnet

Cidofovir

Herpes Virus

~100 known herpes viruses

8 recognized human herpes viruses (HHV)

All 8 are morphologically similar

Lipid envelope w/ glycoprotein protrusions

100nm icosahedral capsid

Internal core of linear D.S DNA

Spectrum of Activity of Anti-Herpes Agents

Acyclovir: most active against HSV-1 & HSV-2 ; Some activity against VZV & EBV (Epstein-Barr Virus)

Ganciclovir & Valacyclovir: Potent against CMV (~100x > active than acyclovir) ; active against ALL HSV, VZV, EBV, HHV6 & HHV8 (< active against acyclovir-resistant HSV)

Foscarnet: Active against DNA & RNA viruses esp. HIV, CMV, EBV, VZV, HHV-6 and ALL HSV (acyclovir resistant)

Cidofovir: Active against HSV, CMV, EBV, papilloma, pox & adenovirus

Aciclovir, Ganciclovir & Valganciclovir

Guanosine analogues

MOA

Inhibits viral DNA synthesis

Triphosphate form compete with dGTP for viral DNA polymerase

Chain termination

Viral DNA polymerase is much more SUSCEPTIBLE to its effects than cellular DNA (Drug more selective for thymidine kinase -> lower attack to human cells)

Polymerase monophosphorylation is catalyzed by a phosphotransferase in CMV & by thymidine kinase in HSV cells

MOR

Lower activity of thymidine kinase

Alteration in viral thymidine kinase

Altered DNA/mutation in polymerase

Reduction in drug-phosphorylation

3 levels of cellular selectivity

  1. Preferentially taken up by INFECTED CELLS
  1. Phosphorylated by VIRAL THYMIDINE KINASE
  1. Di- and Tri-phosphorylated by host celullar enzyme

Viral DNA polymerase incorporate false nucleotide into DNA & terminates synthesis

MOA

Oral, IV, topical formulation

Fairly poor oral & topical absorption (15-30%)

Concentration in Zoster vesicles fluid = in that of plasma

Crosses placenta & enters breast milk (conc. 3x higher than maternal serum)

T1/2: 3-4hours

Excretion: Renal excretion (60-90% UNCHANGED)

Valaciclovir

Amino acid ester prodrug of aciclovir

Oral bioavailability 50% (3-5x higher than aciclovir)

Hydrolyzed in liver & small intestine to aciclovir

Ganciclovir & Valganciclovir

MOA: Oral, IV

Poor oral bioavailability (5-9%) -> large oral doses/IV

Valganciclovir (ester prodrug) better absorbed (B.A 60%)

Metabolized by intestinal & hepatic esterases to ganciclovir

T1/2: 2-4 hours

Renal Excretion (UNCHANGED)

Adverse effects

N/V/GI disturbances (Aciclovir & Valganciclovir)

Rash, headache (Aciclovir & Valganciclovir)

Nephrotoxicity (rare & reversible with Aciclovir)

Myelosuppression (Ganciclovir & Valganciclovir) ; Leukopenia 40%; Thrombocytopenia 20%; Mainly IV

Pyrophosphate analogue (non-nucleoside)

MOA: Directly inhibits pyrophosphate binding site at viral DNA & RNA polymerase (no prior activation by phosphorylation) -> blocks the incorporation of dNTPs into viral DNA

MOR: Mutation of viral DNA polymerase; No cross-resistance w/ acyclovir & ganciclovir

Pharmacokinetics (ADME)

Oral BA 20%

10-20% sequestered in bone w/ gradual release

T1/2: 4-8 hours

Renal clearance (mostly UNCHANGED)

Adverse effects

Nephrotoxicity (25% Most common ADR, reversible)

Hypo-/hypercalcemia (chelates divalent cations)

Hypo-/Hyperphosphatemia

CNS toxicities (hallucinations, seizures, headache

Phosphorylated acyclic cytosine analogue

MOA

Additionally phosphorylated to active metabolite, cidafovir diphosphate (CELLULAR ENZYMES) -> Diphosphate, inhibitor of viral DNA polymerase -> Intefere viral DNA synthesis

MOR

Cidofovir does not rely on viral kinases for phosphorylation & development of resistance may be more difficult

Mutation in viral DNA polymerase gene

Pharmacokinetics

Poor oral BA -> IV

T1/2: 2.6 hours but active diphosphate intracellular T1/2: 17-65 hours

Renal excretion (Mostly UNCHANGED)

Adverse effects

Nephrotoxicity -> prehydrate

Uveitis/ iritis, rash

Neutropenia, GI intolerance

Drug2 Interactions

  • nephrotoxic drugs = Higher nephrotoxicity

Synergism with ganciclovir & foscarnet against CMV

Other Antiviral Agents

Ribavirin (Copegus/Rebetol)

Guanosine analog

Spectrum of Activity

Broad spectrum: against wide range of DNA & RNA viruses inc. influenza A & B, RSV (Respiratory syncytial virus), measles, mumps, Hepatitis C & HIV-1

MOA

Multiple action sites

Inhibit viral mRNA synthesis

Undergoes triple phosphorylation by host cell enzymes

Monophosphate blocks GTP synthesis

Triphosphate inhibits GTP-dependent enzymes

Pharmacokinetics

MOA: Oral, IV, inhalation

Oral BA 50-65% (fatty food higher absorption)

T1/2 varies (200-300 hours at steady state)

Extensively taken up by cells (RBC)

Metabolism by Liver & excretion renal

Adverse effects

Oral & IV: Dose-related & reversible hemolytic anemia

Aerosol: conjunctival irritation, rash, wheezing

Drug2 interaction

  • Inteferon alpha-2b = synergism against Hepatitis C

Inhibits activity of pyrimidine nucleoside HIV RT inhibitors (Zidovudine)

Higher activity of purine nucleoside HIV RT inhibitors (DDI)

Inteferons

Naturally occurring proteins synthesised by mammalian cells in response to viral exposure

Now produced by recombinant DNA technology

Alpha, Beta & Gamma

3 Types of acvitity: Antiviral, ummunomodulatory & antiproliferative

IFN alpha & beta have more antiviral activity than immunomodulatory effects; IFN gamma has predominantly immunomodulatory effects

Spectrum of Activity

Broad spectrum anti-viral activity

Active against DNA viruses (HSV-1 & -2, VZV, HPV) & RNA viruses (influenza & hepatitis)

IFN alpha-2a, alpha-2b & alpha n-1 for Hepatitis B & Hepatitis C