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Vol. 96, Issue 15, 8675-8680, July 20, 1999

Medical Sciences
JE-2147: A dipeptide protease inhibitor (PI) that potently inhibits multi-PI-resistant HIV-1

Kazuhisa Yoshimura^*, Ryohei Kato^*,,, Keisuke Yusa^*, Mark F. Kavlick^*, Victor Maroun^*, Aline Nguyen^*, Tsutomu Mimoto, Takamasa Ueno, Makoto Shintani, Judith Falloon^§, Henry Masur^§, Hideya Hayashi, John Erickson, and Hiroaki Mitsuya^*,¶,,**

^* Experimental Retrovirology Section, Medicine Branch, Division of Clinical Sciences, National Cancer Institute and ^§ Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD 20892;  Structural Biochemistry Program and ^¶ HIV Clinical Interface Laboratory, Developmental Therapeutics Program, Science Applications International Corporation/National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, MD 21702;  Pharmaceuticals and Biotechnology Laboratory, Japan Energy Corporation, Saitama 335 Japan; and  Department of Internal Medicine II, Kumamoto University School of Medicine, Kumamoto 860, Japan

Edited by Peter K. Vogt, The Scripps Research Institute, La Jolla, CA, and approved May 18, 1999 (received for review April 20, 1999)

We designed, synthesized, and identified JE-2147, an allophenylnorstatine-containing dipeptide HIV protease inhibitor (PI), which is potent against a wide spectrum of HIV-1, HIV-2, simian immunodeficiency virus, and various clinical HIV-1 strains in vitro. Drug-resistant clinical HIV-1 strains, isolated from seven patients who had failed 9-11 different anti-HIV therapeutics after 32-83 months, had a variety of drug-resistance-related amino acid substitutions and were highly and invariably resistant to all of the currently available anti-HIV agents. JE-2147 was, however, extremely potent against all such drug-resistant strains, with IC₅₀ values ranging from 13-41 nM (<2-fold changes in IC₅₀ compared with that of wild-type HIV-1). The emergence of JE-2147-resistant HIV-1 variants in vitro was substantially delayed compared with that of HIV-1 resistant to another allophenylnorstatine-containing compound, KNI-272, and other related PIs. Structural analysis revealed that the presence of a flexible P2' moiety is important for the potency of JE-2147 toward wild-type and mutant viruses. These data suggest that the use of flexible components may open a new avenue for designing PIs that resist the emergence of PI-resistant HIV-1. Further development of JE-2147 for treating patients harboring multi-PI-resistant HIV-1 is warranted.

Copyright © 1999 by The National Academy of Sciences  0027-8424/99/968675-6$2.00/0
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