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.

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@article{Lin2003ASM, title={A small molecule HIV-1 inhibitor that targets the HIV-1 envelope and inhibits CD4 receptor binding.}, author={Pin-fang Lin and Wade S. Blair and Tao Wang and Timothy P. Spicer and Qi Hao Guo and Nannan Zhou and Y F Gong and H H Wang and Ronald E. Rose and Gregory A Yamanaka and Brett S Robinson and Chang-ben Li and Robert A Fridell and Carol Deminie and Gwendeline Demers and Zheng Yang and Lisa M Zadjura and Nicholas A. Meanwell and R. J. Colonno}, journal={Proceedings of the National Academy of Sciences of the United States of America}, year={2003}, volume={100 19}, pages={11013-8} }