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Antimicrobial Agents and Chemotherapy, August 2000, p. 2093-2099, Vol. 44, No. 8
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

BMS-232632, a Highly Potent Human Immunodeficiency Virus Protease Inhibitor That Can Be Used in Combination with Other Available Antiretroviral Agents

Brett S. Robinson,1 Keith A. Riccardi,1 Yi-fei Gong,1 Qi Guo,1 David A. Stock,1 Wade S. Blair,1 Brian J. Terry,1 Carol A. Deminie,1 Fred Djang,1 Richard J. Colonno,1 and Pin-fang Lin1,*

Department of Virology and Non-Clinical Biostatistics, Bristol-Myers Squibb Company, Wallingford, Connecticut 064921

Received 16 July 1999/Returned for modification 13 October 1999/Accepted 7 April 2000

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 (EC50) of 2.6 to 5.3 nM and an EC90 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.

* Corresponding author. Mailing address: Bristol-Myers Squibb Co., 5 Research Pkwy., Wallingford, CT 06492. Phone: (203) 677-6437. Fax: (203) 677-6088. E-mail: linp{at}bms.com.

Antimicrobial Agents and Chemotherapy, August 2000, p. 2093-2099, Vol. 44, No. 8
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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