title: A small molecule HIV-1 inhibitor that targets the HIV-1 envelope and inhibits CD4 receptor binding.
abstract: BMS-378806 is a recently discovered small molecule HIV-1 inhibitor that blocks viral entrance to cells. The compound exhibits potent inhibitory activity against a panel of R5-(virus using the CCR5 coreceptor), X4-(virus using the CXCR4 coreceptor), and R5/X4 HIV-1 laboratory and clinical isolates of the B subtype (median EC50 of 0.04 microM) in culture assays. BMS-378806 is selective for HIV-1 and inactive against HIV-2, SIV and a panel of other viruses, and exhibits no significant cytotoxicity in the 14 cell types tested (concentration for 50% reduction of cell growth, >225 microM). Mechanism of action studies demonstrated that BMS-378806 binds to gp120 and inhibits the interactions of the HIV-1 envelope protein to cellular CD4 receptors. Further confirmation that BMS-378806 targets the envelope in infected cells was obtained through the isolation of resistant variants and the mapping of resistance substitutions to the HIV-1 envelope. In particular, two substitutions, M426L and M475I, are situated in the CD4 binding pocket of gp120. Recombinant HIV-1 carrying these two substitutions demonstrated significantly reduced susceptibility to compound inhibition. BMS-378806 displays many favorable pharmacological traits, such as low protein binding, minimal human serum effect on anti-HIV-1 potency, good oral bioavailability in animal species, and a clean safety profile in initial animal toxicology studies. Together, the data show that BMS-378806 is a representative of a new class of HIV inhibitors that has the potential to become a valued addition to our current armamentarium of antiretroviral drugs.
authors.affiliation: Department of Virology, Bristol-Myers Squibb, Wallingford, CT 06492, USA. pinfang.lin@bms.com
authors.forename: Pin-Fang
authors.initials: PF
authors.lastname: Lin
authors.forename: Wade
authors.initials: W
authors.lastname: Blair
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Timothy
authors.initials: T
authors.lastname: Spicer
authors.forename: Qi
authors.initials: Q
authors.lastname: Guo
authors.forename: Nannan
authors.initials: N
authors.lastname: Zhou
authors.forename: Yi-Fei
authors.initials: YF
authors.lastname: Gong
authors.forename: H-G Heidi
authors.initials: HG
authors.lastname: Wang
authors.forename: Ronald
authors.initials: R
authors.lastname: Rose
authors.forename: Gregory
authors.initials: G
authors.lastname: Yamanaka
authors.forename: Brett
authors.initials: B
authors.lastname: Robinson
authors.forename: Chang-Ben
authors.initials: CB
authors.lastname: Li
authors.forename: Robert
authors.initials: R
authors.lastname: Fridell
authors.forename: Carol
authors.initials: C
authors.lastname: Deminie
authors.forename: Gwendeline
authors.initials: G
authors.lastname: Demers
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yang
authors.forename: Lisa
authors.initials: L
authors.lastname: Zadjura
authors.forename: Nicholas
authors.initials: N
authors.lastname: Meanwell
authors.forename: Richard
authors.initials: R
authors.lastname: Colonno
mesh_terms: D000818:Animals; D015704:CD4 Antigens / Q000378:metabolism*; D002460:Cell Line; D004285:Dogs; D023581:HIV Fusion Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects*; D008252:Macaca fascicularis; D010879:Piperazines / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats
chemical_list: C477855:BMS-378806; D015704:CD4 Antigens; D023581:HIV Fusion Inhibitors; D010879:Piperazines