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PMID: 9094684 Published · ppublish English Journal Article

Molecular mechanism underlying the action of a novel fusion inhibitor of influenza A virus.

Journal of virology ·Vol. 71 ·No. 5 ·1997-05-00 ·Pages 4062-70

Luo G, Torri A, Harte WE, Danetz S, Cianci C, Tiley L, Day S, Mullaney D, Yu KL, Ouellet C, Dextraze P, Meanwell N, Colonno R, Krystal M

Abstract

In the initial stages of influenza virus infection, the hemagglutinin (HA) protein of influenza virus mediates both adsorption and penetration of the virus into the host cell. Recently, we identified and characterized BMY-27709 as an inhibitor of the H1 and H2 subtypes of influenza A virus that specifically inhibits the HA function necessary for virus-cell membrane fusion (G.-X. Luo, R. Colonno, and M. Krystal, Virology 226:66-76, 1996). Studies presented herein show that the inhibition is mediated through specific interaction with the HA protein. This binding represses the low-pH-induced conformational change of the HA protein which is a prerequisite for membrane fusion. In an attempt to define the binding pocket within the HA molecule, a number of drug-resistant viruses have been isolated and characterized. Sequence analyses of the HA gene of these drug-resistant viruses mapped amino acid changes responsible for drug resistance to a region located near the amino terminus of HA2. In addition, we have identified inactive analogs of BMY-27709 which are able to compete out the inhibitory activity of BMY-27709. This finding suggests that inhibition of the HA-mediated membrane fusion by this class of compounds is not solely the result of binding within the HA molecule but requires specific interactions.

MeSH Terms
Animals Antiviral Agents/pharmacology Cattle Cell Line Hemagglutinin Glycoproteins, Influenza Virus/chemistry,drug effects,physiology Hydrogen-Ion Concentration Influenza A virus/drug effects,genetics Membrane Fusion/drug effects Phenotype Protein Conformation Quinolizines/pharmacology Structure-Activity Relationship Trypsin/pharmacology
Chemicals
Antiviral Agents BMY 27709 Hemagglutinin Glycoproteins, Influenza Virus Quinolizines Trypsin
Authors & Affiliations
14 authors, click to expand affiliations / ORCID
Luo G
Department of Virology, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut 06492, USA. Guangxiang_Luo@ccmail.bms.com
Torri A
Harte W E
Danetz S
Cianci C
Tiley L
Day S
Mullaney D
Yu K L
Ouellet C
Dextraze P
Meanwell N
Colonno R
Krystal M
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Article Info
Journal
Journal of virology
Abbr.
J Virol
ISSN
0022-538X
DOI
10.1128/JVI.71.5.4062-4070.1997
Email
guangxiang_luo@ccmail.bms.com
Published
1997-05-00
Pages
4062-70
Language
English
Region
United States
NLM ID
0113724
PMCID
PMC191559
Subset
IM
External Links
PubMed source DOI: 10.1128/JVI.71.5.4062-4070.1997 PMC Full Text View journal details
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