A small molecule HIV-1 inhibitor that targets the HIV-1 envelope and inhibits CD4 receptor binding.
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.
Lin
Pin-Fang
PF
Department of Virology, Bristol-Myers Squibb, Wallingford, CT 06492, USA. pinfang.lin@bms.com
Blair
Wade
W
Wang
Tao
T
Spicer
Timothy
T
Guo
Qi
Q
Zhou
Nannan
N
Gong
Yi-Fei
YF
Wang
H-G Heidi
HG
Rose
Ronald
R
Yamanaka
Gregory
G
Robinson
Brett
B
Li
Chang-Ben
CB
Fridell
Robert
R
Deminie
Carol
C
Demers
Gwendeline
G
Yang
Zheng
Z
Zadjura
Lisa
L
Meanwell
Nicholas
N
Colonno
Richard
R
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
C477855:BMS-378806; D015704:CD4 Antigens; D023581:HIV Fusion Inhibitors; D010879:Piperazines