Molecular mechanism underlying the action of a novel fusion inhibitor of influenza A virus.
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.
Luo
G
G
Department of Virology, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut 06492, USA. Guangxiang_Luo@ccmail.bms.com
Torri
A
A
Harte
W E
WE
Danetz
S
S
Cianci
C
C
Tiley
L
L
Day
S
S
Mullaney
D
D
Yu
K L
KL
Ouellet
C
C
Dextraze
P
P
Meanwell
N
N
Colonno
R
R
Krystal
M
M
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002417:Cattle; D002460:Cell Line; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000737:chemistry / Q000187:drug effects* / Q000502:physiology; D006863:Hydrogen-Ion Concentration; D009980:Influenza A virus / Q000187:drug effects* / Q000235:genetics; D008561:Membrane Fusion / Q000187:drug effects; D010641:Phenotype; D011487:Protein Conformation; D011807:Quinolizines / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014357:Trypsin / Q000494:pharmacology
D000998:Antiviral Agents; C105257:BMY 27709; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D011807:Quinolizines; D014357:Trypsin