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Activities, Crystal Structures, and Molecular Dynamics of Dihydro-1H-isoindole Derivatives, Inhibitors of HIV-1 Integrase

DOI: 10.1021/cb300471n DOI Help
PMID: 23075516 PMID Help

Authors: Mathieu Métifiot (National Institutes of Health) , Kasthuraiah Maddali (National Institutes of Health) , Barry C. Johnson (National Institutes of Health) , Stephen Hare (Imperial College London) , Steven J. Smith (National Institutes of Health) , Xue Zhi Zhao (Cancer Research UK) , Christophe Marchand (National Institutes of Health) , Terrence R. Burke (Cancer Research UK) , Stephen H. Hughes (National Institutes of Health) , Peter Cherepanov (Imperial College London) , Yves Pommier (National Institutes of Health)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acs Chemical Biology , VOL 8 (1)

State: Published (Approved)
Published: December 2012

Abstract: On the basis of a series of lactam and phthalimide derivatives that inhibit HIV-1 integrase, we developed a new molecule, XZ-259, with biochemical and antiviral activities comparable to raltegravir. We determined the crystal structures of XZ-259 and four other derivatives in complex with the prototype foamy virus intasome. The compounds bind at the integrase-Mg2+-DNA interface of the integrase active site. In biochemical and antiviral assays, XZ-259 inhibits raltegravir-resistant HIV-1 integrases harboring the Y143R mutation. Molecular modeling is also presented suggesting that XZ-259 can bind in the HIV-1 intasome with its dimethyl sulfonamide group adopting two opposite orientations. Molecular dynamics analyses of the HIV-1 intasome highlight the importance of the viral DNA in drug potency

Journal Keywords: Crystallography; X-Ray; HIV; Humans; Inhibitory; Isoindoles; Molecular; Sulfonamides

Subject Areas: Biology and Bio-materials


Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography

Other Facilities: SLS