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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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