ANTIVIRAL AGENTS FOR THE PREVENTION AND TREATMENT OF INFLUENZA

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ANTIVIRAL AGENTS FOR THE PREVENTION AND TREATMENT
OF INFLUENZA
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Neuraminidase inhibitors
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Viral hemagglutinin binds to cellular sialic
acid

• Binding to Sialic Acid

B. Engulfing Virus
C. Uncoating and Virus Replication
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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.
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Neuraminidase inhibitors Mode of action
Progeny virusesreleased from cell
NeuraminidaseInhibition
Engulfing Virus
Replication
Neuraminidase inhibitors block the active site of
the enzyme and prevent release of virus from
infected cells
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Neuraminidase A conserved site of action
Type AB
H1N1
H2N2
H3N2
H5N1
H9N2
H7N2
Neuraminidases inhibitors are active against
influenza viruses carrying all the known
hemagglutinin and neuraminidase subtypes
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Influenza neuraminidase inhibitors
zanamivir (1980)
oseltamivir (1996)
structure-baseddesign
2000s
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Zanamivir
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Oseltamivir
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The prodrug concept and oral bioavailability
O
O
O
O
O
OH
Ester hydrolysis
HN
HN
NH2H3PO4
NH2
O
O
Oseltamivir phosphate
Oseltamivir carboxylate

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

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Committee on influenzawww.apaci-flu.com