title: Biochemical and genetic characterizations of a novel human immunodeficiency virus type 1 inhibitor that blocks gp120-CD4 interactions.
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.
authors.affiliation: Department of Virology, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut 06492, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Guo
authors.forename: Hsu-Tso
authors.initials: HT
authors.lastname: Ho
authors.forename: Ira
authors.initials: I
authors.lastname: Dicker
authors.forename: Li
authors.initials: L
authors.lastname: Fan
authors.forename: Nannan
authors.initials: N
authors.lastname: Zhou
authors.forename: Jacques
authors.initials: J
authors.lastname: Friborg
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Brian V
authors.initials: BV
authors.lastname: McAuliffe
authors.forename: Hwei-Gene Heidi
authors.initials: HG
authors.lastname: Wang
authors.forename: Ronald E
authors.initials: RE
authors.lastname: Rose
authors.forename: Hua
authors.initials: H
authors.lastname: Fang
authors.forename: Helen T
authors.initials: HT
authors.lastname: Scarnati
authors.forename: David R
authors.initials: DR
authors.lastname: Langley
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Meanwell
authors.forename: Ralph
authors.initials: R
authors.lastname: Abraham
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Colonno
authors.forename: Pin-Fang
authors.initials: PF
authors.lastname: Lin
mesh_terms: 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*
chemical_list: D019380:Anti-HIV Agents; C477855:BMS-378806; D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D010879:Piperazines