Biochemical and genetic characterizations of a novel human immunodeficiency virus type 1 inhibitor that blocks gp120-CD4 interactions.
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.
Guo
Qi
Q
Department of Virology, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut 06492, USA.
Ho
Hsu-Tso
HT
Dicker
Ira
I
Fan
Li
L
Zhou
Nannan
N
Friborg
Jacques
J
Wang
Tao
T
McAuliffe
Brian V
BV
Wang
Hwei-Gene Heidi
HG
Rose
Ronald E
RE
Fang
Hua
H
Scarnati
Helen T
HT
Langley
David R
DR
Meanwell
Nicholas A
NA
Abraham
Ralph
R
Colonno
Richard J
RJ
Lin
Pin-Fang
PF
D000818:Animals; D019380:Anti-HIV Agents / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D001667:Binding, Competitive; D015704:CD4 Antigens / Q000378:metabolism*; D002460:Cell Line; D006224:Cricetinae; D015699:HIV Envelope Protein gp120 / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects*; D051379:Mice; D010879:Piperazines / Q000494:pharmacology*
D019380:Anti-HIV Agents; C477855:BMS-378806; D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D010879:Piperazines