title: BMS-232632, a highly potent human immunodeficiency virus protease inhibitor that can be used in combination with other available antiretroviral agents.
abstract: BMS-232632 is an azapeptide human immunodeficiency virus type 1 (HIV-1) protease (Prt) inhibitor that exhibits potent anti-HIV activity with a 50% effective concentration (EC(50)) of 2.6 to 5.3 nM and an EC(90) of 9 to 15 nM in cell culture. Proof-of-principle studies indicate that BMS-232632 blocks the cleavage of viral precursor proteins in HIV-infected cells, proving that it functions as an HIV Prt inhibitor. Comparative studies showed that BMS-232632 is generally more potent than the five currently approved HIV-1 Prt inhibitors. Furthermore, BMS-232632 is highly selective for HIV-1 Prt and exhibits cytotoxicity only at concentrations 6,500- to 23, 000-fold higher than that required for anti-HIV activity. To assess the potential of this inhibitor when used in combination with other antiretrovirals, BMS-232632 was evaluated for anti-HIV activity in two-drug combination studies. Combinations of BMS-232632 with either stavudine, didanosine, lamivudine, zidovudine, nelfinavir, indinavir, ritonavir, saquinavir, or amprenavir in HIV-infected peripheral blood mononuclear cells yielded additive to moderately synergistic antiviral effects. Importantly, combinations of drug pairs did not result in antagonistic anti-HIV activity or enhanced cytotoxic effects at the highest concentrations used for antiviral evaluation. Our results suggest that BMS-232632 may be an effective HIV-1 inhibitor that may be utilized in a variety of different drug combinations.
authors.affiliation: Department of Virology and Non-Clinical Biostatistics, Bristol-Myers Squibb Company, Wallingford, Connecticut 06492, USA.
authors.forename: B S
authors.initials: BS
authors.lastname: Robinson
authors.forename: K A
authors.initials: KA
authors.lastname: Riccardi
authors.forename: Y F
authors.initials: YF
authors.lastname: Gong
authors.forename: Q
authors.initials: Q
authors.lastname: Guo
authors.forename: D A
authors.initials: DA
authors.lastname: Stock
authors.forename: W S
authors.initials: WS
authors.lastname: Blair
authors.forename: B J
authors.initials: BJ
authors.lastname: Terry
authors.forename: C A
authors.initials: CA
authors.lastname: Deminie
authors.forename: F
authors.initials: F
authors.lastname: Djang
authors.forename: R J
authors.initials: RJ
authors.lastname: Colonno
authors.forename: P F
authors.initials: PF
authors.lastname: Lin
mesh_terms: D000069446:Atazanavir Sulfate; D001798:Blood Proteins; D002478:Cells, Cultured; D004338:Drug Combinations; D004347:Drug Interactions; D015683:Gene Products, gag / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D008826:Microbial Sensitivity Tests; D009842:Oligopeptides / Q000494:pharmacology*; D011498:Protein Precursors / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*
chemical_list: D001798:Blood Proteins; D004338:Drug Combinations; D015683:Gene Products, gag; D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D011498:Protein Precursors; D011725:Pyridines; D018894:Reverse Transcriptase Inhibitors; C059767:p55 gag precursor protein, Human immunodeficiency virus 1; D000069446:Atazanavir Sulfate