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A potent human immunodeficiency virus type 1 protease inhibitor, UIC-94003 (TMC-126), and selection of a novel (A28S) mutation in the protease active site

  1. Author:
    Yoshimura, K.
    Kato, R.
    Kavlick, M. F.
    Nguyen, A.
    Maroun, V.
    Maeda, K.
    Hussain, K. A.
    Ghosh, A. K.
    Gulnik, S. V.
    Erickson, J. W.
    Mitsuya, H.

  2. Author Address

    NCI, Expt Retrovirol Sect, Med Branch, Div Clin Sci, NIH, Bldg 10, Rm 5A11, Bethesda, MD 20892 USA. NCI, Expt Retrovirol Sect, Med Branch, Div Clin Sci, NIH, Bethesda, MD 20892 USA. Kumamoto Univ, Sch Med, Dept Internal Med 2, Kumamoto 8608556, Japan. Univ Illinois, Dept Chem, Chicago, IL 60607 USA. NCI, Frederick Canc Res & Dev Ctr, Struct Biochem Program, SAIC, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, HIV Clin Interface Lab, Dev Therapeut Program, SAIC, Frederick, MD 21702 USA. Mitsuya H NCI, Expt Retrovirol Sect, Med Branch, Div Clin Sci, NIH, Bldg 10, Rm 5A11, Bethesda, MD 20892 USA.
    1. Year: 2002
  2. Journal: Journal of Virology
    1. 76
    2. 3
    3. Pages: 1349-1358
  4. Type of Article: Article
  1. Abstract:

    We identified UIC-94003, a nonpeptidic human immunodeficiency virus (HIV) protease inhibitor (PI), containing 3(R),3a(S),6a(R)-bis-tetrahydrofuranyl urethane (bis-THF) and a sulfonamide isostere, which is extremely potent against a wide spectrum of HIV (50% inhibitory concentration, 0.0003 to 0.0005 muM). UIC-94003 was also potent against multi-PI-resistant HIV- 1 strains isolated from patients who had no response to any existing antiviral regimens after having received a variety of antiviral agents (50% inhibitory concentration, 0.0005 to 0.0055 muM). Upon selection of HIV-1 in the presence of UIC- 94003, mutants carrying a novel active-site mutation, A28S, in the presence of L10F, M46I, I50V, A71V, and N88D appeared. Modeling analysis revealed that the close contact of UIC-94003 with the main chains of the protease active-site amino acids (Asp29 and Asp30) differed from that of other PIs and may be important for its potency and wide spectrum activity against a variety of drug-resistant HIV-1 variants. Thus, introduction of inhibitor interactions with the main chains of key amino acids and seeking a unique inhibitor-enzyme contact profile should provide a framework for developing novel PIs for treating patients harboring multi-PI-resistant HIV-1.

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