BMS-232632, a highly potent human immunodeficiency virus protease inhibitor that can be used in combination with other available antiretroviral agents

BMS-232632 is an azapeptide human immunodeficiency virus type 1 (HIV-1) pro tease (Prt) inhibitor that exhibits potent anti-HIV activity with a 50% eff ective concentration (EC50) of 2.6 to 5.3 nM and an EC90 of 9 to 15 nM in c ell culture. Proof-of-principle studies indicate that BMS-232632 blocks the cleavage of viral precursor proteins in HIV-infected cells, proving that i t functions as an HIV Prt inhibitor. Comparative studies showed that BMS-23 2632 is generally more potent than the five currently approved HIV-1 Prt in hibitors. Furthermore, BMS-232632 is highly selective for HIV-1 Prt and exh ibits cytotoxicity only at concentrations 6,500- to 23,000-fold higher than that required for anti-HIV activity. To assess the potential of this inhib itor when used in combination with other antiretrovirals, BMS-232632 was ev aluated for anti-HIV activity in two-drug combination studies. Combinations of BMS-232632 with either stavudine, didanosine, lamivudine, zidovudine, n elfinavir, indinavir, ritonavir, saquinavir, or amprenavir in HN-infected p eripheral blood mononuclear cells yielded additive to moderately synergisti c antiviral effects. Importantly, combinations of drug pairs did not result in antagonistic anti-HIV activity or enhanced cytotoxic effects at the hig hest concentrations used for antiviral evaluation. Our results suggest that BMS-232632 may be an effective HIV-1 inhibitor that may be utilized in a v ariety of different drug combinations.