Antiviral Agents

Upton D. Allen

Outline of Presentation

• Herpes group agents

• Anti-influenza agents

• Anti-hepatitis agents

• Anti-RSV

• Immune response modifiers

• Other

From acyclovir to...

Zanamivir…

Antiviral Agents for Herpes Viruses

• Acyclovir / Valacyclovir • Ganciclovir / Valganciclovir• Famciclovir / Penciclovir• Cidofovir• Foscarnet• Trifluridine• Vidarabine

Antivirals of Choice for Herpes Group Viruses

• HSV Acyclovir • VZV Acyclovir • EBV Ganciclovir • CMV Ganciclovir; Foscarnet• HHV-6 Foscarnet; Ganciclovir• HHV-7 Cidofovir• HHV-8 Cidofovir most potent

Antiviral Agents: Acyclovir, Valacyclovir, Famciclovir

Valacyclovir is a prodrug of acyclovir;

Oral bioavailability of acyclovir from valacyclovir is 54% as compared to 15-30% for acyclovir.

Famciclovir is a prodrug for the active metabolite penciclovir; mean oral bioavailability of penciclovir from famciclovir is 77%.

Penciclovir and acyclovir are primarily eliminated unchanged by the kidneys and have mean half-lives of 2.5 hours.

Nucleoside analogs - Antimetabolites

HN

N N

N

O

H2NO

HO

OHHO

Guanosine

Aciclovir®Zovirax®Valtrex®

Guanosine analogActivity: DNA Herpes viruses(Herpes simplex, varicella, CMV, Epstein Barr)

HN

N N

N

O

H2NO

HO

Acyclovir

HN

N N

N

O

H2NO

O

Valacyclovir

ONH

Increase GI absorbtion

N

N N

N

H2NO

HO

6-Deoxyacyclovir

Esterases

Increased solubility

Xanthine oxidase

Adenosine deaminase

N

N N

N

H2NO

HO

NH2

Mechanism of Action of Acyclovir

Mechanism of Action of Acyclovir

• Acyclovir molecules enter cell • Converted to acyclovir monophosphate by the HSV enzyme thymidine kinase (TK). • Cellular enzymes result in active drug acyclovir triphosphate. • Acyclovir triphosphate competes with 2- deoxyguanosine triphosphate (dGTP) as a substrate for viral DNA polymerase, as well as acting as a chain terminator.

Trifluridine

Trifluridine - fluorinated pyrimidine inhibits viral DNA synthesis same as acyclovir

incorporates into viral and cellular DNA

Uses: HSV-1 and HSV-2 (topically)

Vidarabine

An adenosine analog

inhibits viral DNA polymerase

incorporated into viral and cellular DNA

metabolized to hypoxanthine arabinoside

Side Effects: GI intolerance and myelosuppression

Antiviral Agents for Herpes Viruses

• Acyclovir / Valacyclovir • Ganciclovir / Valganciclovir• Famciclovir / Penciclovir• Cidofovir• Foscarnet• Trifluridine• Vidarabine

HN

N N

N

O

H2NO

HO

Gancyclovir

HN

N N

N

O

H2NO

O

Valgancyclovir

ONH

Esterases

HOHO

O,N-acetal

Cymevene®Valcyte®

HN

N N

N

O

H2N

HO

Peniciclovir

HO

More stableLow oral availability

Xanthine oxidaseEsterases

N

N N

N

H2N

AcO

Famciclovir

AcO

•Converted to triphosphates•Inhibitors of viral DNA polymerases

Extracellular

Intracellular

GCV GCV-MP GCV-DP GCV-TP

CellularEnzymes

Inhibits Viral DNA Polymerase

(UL54 encoded)

Mechanism of Ganciclovir Resistance

ViralProtein Kinase (UL97 encoded)

Foscarnet - 1

Inhibits DNA polymerase Does not require activation by virally encoded

nucleoside kinases or phosphotransferases.

Foscarnet - 2

Foscarnet’s Selectivity

100-fold greater inhibitory effects against herpesvirus DNA polymerase compared with cellular DNA polymerase

Foscarnet - Toxicity

Renal Significant magnesium wasting CNS (tremor or seizures) notably in patients

receiving calcineurin inhibitors.

Cidofovir -1

Nucleotide analog requires cellular phosphotransferases for activation

Does not require activation by virally encoded thymidine kinase or phosphotransferase

Cidofovir -2

Cidofovir-resistant isolates in vitro are cross-resistant to ganciclovir but generally susceptible to foscarnet.

Cidofovir is active against some, but not all CMV isolates that are resistant to foscarnet

Cidofovir — Toxicity

Contraindicated in patients with renal impairment

Contraindicated in patients receiving other nephrotoxic agents

Usually administered with probenecid and hydration to reduce nephrotoxicity

Leflunomide

Immunosuppressive agent used in

treatment of rheumatoid arthritis. Inhibits CMV by impairing late stages of

viral assembly. Has been used in some reports of

ganciclovir or foscarnet resistant CMV.

Valganciclovir

Ganciclovir Time Profiles in HIV Patients

90% plasma GCV Excreted unchanged

In urine; half-life 2-6 hours

Valganciclovir Role in CMV prophylaxis Effective in treating CMV retinitis in AIDS

patients. Emerging data in CMV treatment in

transplantation. Limited data in children Caution in liver transplant recipients

Anti-Hepatitis Agents

Lamivudine -Nucleoside Reverse Transcriptase Inhibitor (NRTI)

Adefovir -Nucleotide Inhibitor

Interferon AlfaPegylated Interferon AlfaRibavirin

Interferons

Interferon Alfa

Endogenous proteins

induce host cell enzymes that inhibit viral RNA translation and cause degradation of viral mRNA and tRNABind to membrane receptors on cell surfaceMay also inhibit viral penetration, uncoating, mRNA synthesis, and translation, and virion assembly and release

Interferons

Pegylated interferon AlfaA linear or branched polyethylene gylcol (PEG) moiety is attached to covalently to interferonIncreased half-life and steady drug concentrationsLess frequent dosingTx 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

Drugs Used to Treat Hepatitis

Anti-Influenza Agents

Amantadine

Rimantadine

Zanamivir

Oseltamivir

Peramivir

Laninamvir

Other

Amantadine and 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

Influenza neuraminidase cleaves terminal sialic acid residues from carbohydrates moieties in the surface of infected cells; destroys receptors recognized by viral hemaglutinin on cells, on newly released virions and on respiratory tract mucins.

Cleaving of sialic acid essential for release of virus from infected cells and for spread with resp tract.

Neuraminidase inhibitors limit spread of virus with resp tract; may prevent virus penetration as well.

Zanamivir and Oseltamivir

Inhibits the enzyme neuraminidase

Inhibit the replication of influenza A and Influenza B

Treats uncomplicated influenza infections

Zanamivir administered by oral inhalation

Oseltamivir administered orally

Resistance due to mutations in HA or NA genes.

Mutations conferring resistance of oseltamivir do not necessarily lead to cross-resistance with zanamivir.

Mechanism of Action of Mechanism of Action of Neuraminidase InhibitorsNeuraminidase Inhibitors

Influenza neuraminidase releases newly formed viruses from infected cells, allowing cell to cell spread.

Neuraminidase inhibitors mimic the natural substrate of the influenza neuraminidase (the sialic acid receptors) and bind to the active site, preventing neuraminidase from cleaving host-cell receptors and releasing virus.

Zanamivir and Oseltamivir

O

CO2H

OGlycopeptide

HO

HN

O

OHHO

HO

NeuraminidaseHO

GlycopeptideO

CO2H

OHHO

HN

O

OHHO

HO

+

Sialic acid≈ SN1

≈ TS‡

Zanamivir Oseltamivir

O

CO2H

OGlycopeptide

HO

HN

O

OHHO

HO

Sialic acid

OCO2H

HO

HN

O

OHHO

HO

OH2

O

CO2HHO

HN

O

OHHO

HO

Lead compound Neuramidinase Inhib. (not selective for viral NA)

DANA

.F.r. .lective dru.g Carbocyclic drug

CO2HH2N

HN

O

OO

CO2HHO

HN

O

OHHO

HO

O

CO2HHN

HN

O

OHHO

HO

HN NH2

Imiqumod (R-837, S-3608)

1-(2-methylpropyl)-1H-imidazo-[4,5-C] quinolin-4-amine

Interferon inducer

Immune-response modifer

Thank You