Transcript G O N I O S C O P Y M A D E E A S Y

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 viruses
released from cell
Neuraminidase
Inhibition
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)
oseltamivir
(1996)
structure-based
design
2000s
Zanamivir
Oseltamivir
Influenza A and B
Influenza A and B
Oral inhalation of powder
Oral capsules or liquid suspension
Effective for treatment and prophylaxis
Effective for treatment and
prophylaxis
Zanamivir
OH
H
HO
O
HO
CH3CONH
CO2H
NH2
NH
NH
Oseltamivir
Oxygen
Nitrogen
The prodrug concept and oral
bioavailability
O
O
O
O
O
Ester
hydrolysis
HN
O
HN
NH2·H3PO4
Oseltamivir phosphate
•
•
•
•
OH
O
NH2
Oseltamivir carboxylate
Prodrug “masks” polarity of active form
Rapid hepatic conversion to active form
Bioavailability: at least 75%
High plasma concentrations
By courtesy of APACI
Asia-Pacific Advisory Committee on influenza
www.apaci-flu.com