HIV-1 integrase strand transfer inhibitors with reduced susceptibility to drug resistant mutant integrases

DOI: 10.1021/acschembio.5b00948

Authors: Xue Zhi Zhao (National Cancer Institute, National Institutes of Health) , Steven J. Smith (National Cancer Institute, National Institutes of Health) , Daniel Maskell (Cancer Research UK) , Mathieu Metifiot (National Cancer Institute, National Institutes of Health, USA) , Valerie Pye (Trinity College Dublin; Cancer Research UK) , Katherine Fesen (National Cancer Institute, National Institutes of Health, USA) , Christophe Marchand (National Cancer Institute, National Institutes of Health, USA) , Yves Pommier (National Cancer Institute, National Institutes of Health, USA) , Peter Cherepanov (Imperial College London; Cancer Research UK) , Stephen H. Hughes (National Cancer Institute, National Institutes of Health, USA) , Terrence R. Burke (National Cancer Institute, National Institutes of Health)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acs Chemical Biology , VOL 11 , PAGES 1074–1081

State: Published (Approved)
Published: February 2016
Diamond Proposal Number(s): 9424

Abstract: HIV integrase (IN) strand transfer inhibitors (INSTIs) are among the newest anti-AIDS drugs; however, mutant forms of IN can confer resistance. We developed noncytotoxic naphthyridine-containing INSTIs that retain low nanomolar IC50 values against HIV-1 variants harboring all of the major INSTI-resistant mutations. We found by analyzing crystal structures of inhibitors bound to the IN from the prototype foamy virus (PFV) that the most successful inhibitors show striking mimicry of the bound viral DNA prior to 3′-processing and the bound host DNA prior to strand transfer. Using this concept of “bi-substrate mimicry,” we developed a new broadly effective inhibitor that not only mimics aspects of both the bound target and viral DNA but also more completely fills the space they would normally occupy. Maximizing shape complementarity and recapitulating structural components encompassing both of the IN DNA substrates could serve as a guiding principle for the development of new INSTIs.

Journal Keywords: Peptides and proteins; Genetics; Crystal structure; Assays; Inhibitors

Diamond Keywords: Human Immunodeficiency Virus (HIV); Viruses; Enzymes

Subject Areas: Biology and Bio-materials, Medicine, Chemistry


Instruments: I02-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography

Other Facilities: SOLEIL

Added On: 24/02/2016 16:50

Documents:
acschembio.5b00948.pdf

Discipline Tags:

Pathogens Infectious Diseases Health & Wellbeing Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)