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Updated: May 29, 2026

Rapid Screening of HIV Reverse Transcriptase and Integrase Inhibitors
Published on: April 9, 2014
MK-0536 inhibits HIV-1 integrases resistant to raltegravir
Mathieu Métifiot1, Barry Johnson, Steven Smith
1Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Drive, Bethesda, Maryland 20892, USA.
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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