ANTIVIRAL AGENTS FOR THE PREVENTION AND

TREATMENT OF INFLUENZA

Neuraminidase inhibitors

Viral hemagglutinin binds to cellular sialic acid

A. Binding to Sialic Acid B. Engulfing Virus C. Uncoating and Virus Replication

Neuraminidase and viral spread

• Permits release of progeny viruses from infected host cells

• Prevents aggregation of newly formed viral particles

• Allows virus to penetrate the mucus of the respiratory tract

Calfee DP, Hayden FG. Drugs 1998; 56: 537-553.Colman PM. Protein Sci 1994; 3: 1687-1695.

Neuraminidase inhibitors: Mode of action

Engulfing Virus Replication Progeny virusesreleased from cell

NeuraminidaseInhibition

Neuraminidase inhibitors block the active site of the enzyme and prevent release of virus from infected cells

Neuraminidase: A conserved site of action

Type A+B

H1N1 H2N2 H3N2 H5N1 H9N2 H7N2

Neuraminidases inhibitors are active against influenza viruses carrying all the known hemagglutinin and neuraminidase subtypes

Influenza neuraminidase inhibitors

zanamivir(1980)

structure-baseddesign

oseltamivir (1996)

2000s

Effective for treatment and prophylaxis

Effective for treatment and prophylaxis

Oral capsules or liquid suspensionOral inhalation of powder

Influenza A and BInfluenza A and B

OseltamivirZanamivir

Zanamivir

HO

HO

HOH

OCO2H

NH2NH

NH

CH3CONH

Oxygen

Nitrogen

Oseltamivir

The prodrug concept and oral bioavailability

• Prodrug “masks” polarity of active form• Rapid hepatic conversion to active form• Bioavailability: at least 75%• High plasma concentrations

Oseltamivir phosphate Oseltamivir carboxylate

O O

O

NH2·H3PO4

O

HN

O

NH2

O

HN

Ester hydrolysis

O OH

By courtesy of APACIAsia-Pacific Advisory Committee on influenzawww.apaci-flu.com