Open AccessBiochemical and Genetic Characterizations of a Novel Human Immunodeficiency Virus Type 1 Inhibitor That Blocks gp120-CD4 Interactions
Author(s) -
Qi Guo,
HsuTso Ho,
Ira B. Dicker,
Li Fan,
Nannan Zhou,
Jacques Friborg,
Tao Wang,
Brian McAuliffe,
Hwei-gene Heidi Wang,
Ronald E. Rose,
Hua Fang,
Helen Scarnati,
David R. Langley,
Nicholas A. Meanwell,
Ralph Abraham,
Richard J. Colonno,
PinFang Lin
Publication year - 2003
Publication title -
journal of virology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.617
H-Index - 292
eISSN - 1070-6321
pISSN - 0022-538X
DOI - 10.1128/jvi.77.19.10528-10536.2003
Subject(s) - biology , entry inhibitor , binding site , plasma protein binding , viral envelope , mutation , small molecule , human immunodeficiency virus (hiv) , viral entry , virology , virus , viral replication , microbiology and biotechnology , biochemistry , gene
BMS-378806 is a recently discovered small-molecule human immunodeficiency virus type 1 (HIV-1) attachment inhibitor with good antiviral activity and pharmacokinetic properties. Here, we demonstrate that the compound targets viral entry by inhibiting the binding of the HIV-1 envelope gp120 protein to cellular CD4 receptors via a specific and competitive mechanism. BMS-378806 binds directly to gp120 at a stoichiometry of approximately 1:1, with a binding affinity similar to that of soluble CD4. The potential BMS-378806 target site was localized to a specific region within the CD4 binding pocket of gp120 by using HIV-1 gp120 variants carrying either compound-selected resistant substitutions or gp120-CD4 contact site mutations. Mapping of resistance substitutions to the HIV-1 envelope, and the lack of compound activity against a CD4-independent viral infection confirm the gp120-CD4 interactions as the target in infected cells. BMS-378806 therefore serves as a prototype for this new class of antiretroviral agents and validates gp120 as a viable target for small-molecule inhibitors.