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
• 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.
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
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.
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
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