title: MK-0536 inhibits HIV-1 integrases resistant to raltegravir.
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.
authors.affiliation: Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Drive, Bethesda, Maryland 20892, USA.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Métifiot
authors.forename: Barry
authors.initials: B
authors.lastname: Johnson
authors.forename: Steven
authors.initials: S
authors.lastname: Smith
authors.forename: Xue Zhi
authors.initials: XZ
authors.lastname: Zhao
authors.forename: Christophe
authors.initials: C
authors.lastname: Marchand
authors.forename: Terrence
authors.initials: T
authors.lastname: Burke
authors.forename: Stephen
authors.initials: S
authors.lastname: Hughes
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
mesh_terms: D024882:Drug Resistance, Viral; D019428:HIV Integrase Inhibitors / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D015394:Molecular Structure; D011760:Pyrrolidinones / Q000494:pharmacology*; D000068898:Raltegravir Potassium; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019428:HIV Integrase Inhibitors; D011760:Pyrrolidinones; D000068898:Raltegravir Potassium