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
