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

  1. Author:
    Yoshimura, K.
    Kato, R.
    Yusa, K.
    Kavlick, M. F.
    Maroun, V.
    Nguyen, A.
    Mimoto, T.
    Ueno, T.
    Shintani, M.
    Falloon, J.
    Masur, H.
    Hayashi, H.
    Erickson, J.
    Mitsuya, H.

  2. Author Address

    Mitsuya H NCI, Expt Retrovirol Sect, Med Branch, Div Clin Sci,NIH Bldg 10,Room 5A11 Bethesda, MD 20892 USA NCI, Expt Retrovirol Sect, Med Branch, Div Clin Sci,NIH Bethesda, MD 20892 USA NIH, Crit Care Med Dept, Ctr Clin Bethesda, MD 20892 USA NCI, Struct Biochem Program, Sci Applicat Int Corp, Frederick Canc Res & Dev Ctr Ft Detrick, MD 21702 USA NCI, HIV Clin Interface Lab,Dev Therapeut Program, Sci Applicat Int Corp, Frederick Canc Res & Dev Ctr Ft Detrick, MD 21702 USA Japan Energy Corp, Pharmaceut & Biotechnol Lab Toda Saitama 335 Japan Kumamoto Univ, Sch Med, Dept Internal Med 2 Kumamoto 860 Japan
    1. Year: 1999
  2. Journal: Proceedings of the National Academy of Sciences of the United States of America
    1. 96
    2. 15
    3. Pages: 8675-8680
  4. Type of Article: Article
  1. 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. [References: 24]

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