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PMID: 12970437 Published · ppublish English Journal Article

Biochemical and genetic characterizations of a novel human immunodeficiency virus type 1 inhibitor that blocks gp120-CD4 interactions.

Journal of virology ·Vol. 77 ·No. 19 ·2003-10-00 ·Pages 10528-36

Guo Q, Ho HT, Dicker I, Fan L, Zhou N, Friborg J, Wang T, McAuliffe BV, Wang HG, Rose RE, Fang H, Scarnati HT, Langley DR, Meanwell NA, Abraham R, Colonno RJ, Lin PF

Abstract

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.

MeSH Terms
Animals Anti-HIV Agents/metabolism,pharmacology Binding Sites Binding, Competitive CD4 Antigens/metabolism Cell Line Cricetinae HIV Envelope Protein gp120/metabolism HIV-1/drug effects Mice Piperazines/pharmacology
Chemicals
Anti-HIV Agents BMS-378806 CD4 Antigens HIV Envelope Protein gp120 Piperazines
Authors & Affiliations
17 authors, click to expand affiliations / ORCID
Guo Qi
Department of Virology, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut 06492, USA.
Ho Hsu-Tso
Dicker Ira
Fan Li
Zhou Nannan
Friborg Jacques
Wang Tao
McAuliffe Brian V
Wang Hwei-Gene Heidi
Rose Ronald E
Fang Hua
Scarnati Helen T
Langley David R
Meanwell Nicholas A
Abraham Ralph
Colonno Richard J
Lin Pin-Fang
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Article Info
Journal
Journal of virology
Abbr.
J Virol
ISSN
0022-538X
DOI
10.1128/jvi.77.19.10528-10536.2003
Published
2003-10-00
Pages
10528-36
Language
English
Region
United States
NLM ID
0113724
PMCID
PMC228513
Subset
IM
External Links
PubMed source DOI: 10.1128/jvi.77.19.10528-10536.2003 PMC Full Text View journal details
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