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MK-0536 Inhibits HIV-1 Integrases Resistant to Raltegravir

  1. Author:
    Metifiot, M.
    Johnson, B.
    Smith, S.
    Zhao, X. Z.
    March, C.
    Burke, T.
    Hughes, S.
    Pommier, Y.

  2. Author Address

    [Metifiot, M; Marchand, C; Pommier, Y] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Johnson, B; Smith, S; Hughes, S] NCI, HIV Drug Resistance Program, Ctr Canc Res, NIH, Frederick, MD 21702 USA. [Zhao, XZ; Burke, T] NCI, Biol Chem Lab, Mol Discovery Program, Ctr Canc Res,NIH, Frederick, MD 21702 USA.;Pommier, Y (reprint author), NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, 37 Convent Dr, Bethesda, MD 20892 USA;pommier@nih.gov
    1. Year: 2011
    2. Date: Nov
  2. Journal: Antimicrobial Agents and Chemotherapy
    1. 55
    2. 11
    3. Pages: 5127-5133
  4. Type of Article: Article
  5. ISSN: 0066-4804
  1. Abstract:

    With the U. S. Food and Drug Administration approval of raltegravir (RAL; MK-0518; Merck & Co.), HIV-1 integrase (IN) is the newest therapeutic target for AIDS and HIV infections. Recent structural analyses show that IN strand transfer inhibitors (INSTIs) share a common binding mode in the enzyme active site. While RAL represents a therapeutic breakthrough, the emergence of IN resistance mutations imposes the development of new INSTIs. We report here the biochemical and antiviral activities of MK-0536, a new IN inhibitor. We demonstrate that, like RAL, MK-0536 is highly potent against recombinant IN and viral replication. It is also effective against INs that carry the three main RAL resistance mutations (Y143R, N155H, and to a lesser extent G140S-Q148H) and against the G118R mutant. Modeling of IN developed from recent prototype foamy virus structures is presented to account for the differences in the drug activities of MK-0536 and RAL against the IN mutants.

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External Sources

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  2. DOI: 10.1128/aac.05288-11
  3. View record in Web of Science®
  4. WOS: 000296375600025

Library Notes

  1. Fiscal Year: FY2011-2012
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