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BMS-663068 is a small-molecule attachment inhibitor of HIV-1 gp120 with IC50 value of [1].

The first step of HIV-1 virus to entry host cells is the binding of the viral gp120 envelope glycopeptide to the CD4 receptor of host cell. BMS-663068 is an attachment inhibitor against specific HIV-1 isolates and targets this step. It is a phosphonooxy methyl prodrug and can be cleaved by alkaline phosphatase in the gut then releases the effective moiety BMS-626529. Compared with the progenitor attachment inhibitorBMS-488043, BMS-663068 has an improved antivirus spectrum [1].

BMS-663068 showed low cytotoxicity in cell culture. In PM1 and PBMC cells, the CC50 values were 105 and 192 μM, respectively. In HEK293, HepG2, HCT116, HeLa, MT-2, MCF-7 and H292 cells, the CC50 values were all higher than 200 μM. It was found that BMS-663068 has potent anti-virus activity against both the laboratory strains and the clinical isolates of HIV. For the CXCR4-tropic LAI virus, BMS-663068 showed EC50 value of 0.7 nM. For a cohort of laboratory strains including NL4-3, SF-162 and JRFL, the inhibition efficacies of BMS-663068 against them were 7 to 10-fold higher than that of BMS-488043. It was even more potent than BMS-488043 when treated with 89.6 viruses (15-fold), Bal virus (14-fold) and MN virus (67-fold). In an antiviral assay using PBMC cells, BMS-663068 was treated against a total of 88 HIV-1 viruses obtained from the NIH AIDS Repository. It exerted an EC50 value of 0.01 nM against the most susceptible virus and an EC50 value of 2μM against the least susceptible virus. In addition, it was found that the virus resistant to other HIV-1 entry inhibitors such as ENF and ibalizumab retained susceptibility to BMS-626529 [1 and 2].

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