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

Content Provider	PubMed Central
Author	Yoshimura, Kazuhisa Kato, Ryohei Yusa, Keisuke Kavlick, Mark F. Maroun, Victor Nguyen, Aline Mimoto, Tsutomu Ueno, Takamasa Shintani, Makoto Falloon, Judith Masur, Henry Hayashi, Hideya Erickson, John Mitsuya, Hiroaki
Copyright Year	1999
Abstract	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.
Starting Page	8675
File Format	PDF
ISSN	10916490
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	15
Volume Number	96
Language	English
Publisher	The National Academy of Sciences
Publisher Date	1999-07-20
Access Restriction	Open
Rights Holder	The National Academy of Sciences
Subject Keyword	Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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