Volume 90 Issue 16 | p. 40 | Concentrates
Issue Date: April 16, 2012

Normal And Mutant HIV Protease Active States Look The Same

Transition-state structures could make good drug targets that overcome protease inhibitor drug resistance
Department: Science & Technology
News Channels: Analytical SCENE, Biological SCENE
Keywords: HIV, protease, protease inhibitor, drug resistance

Native and drug-resistant HIV-1 proteases have similar transition states, a finding that indicates protease inhibitors targeting transition-state interactions should work against both native HIV-1 protease and mutated versions (Proc. Natl. Acad. Sci. USA, DOI: 10.1073/pnas.1202808109). Vern L. Schramm and coworkers at Albert Einstein College of Medicine analyzed the transition states by measuring kinetic isotope effects for 14C, 15N, 18O, and 3H at positions surrounding the substrate cleavage site. Kinetic isotope effects are calculated from the ratio of reaction rates for isotopically labeled substrate peptides. The researchers calculated predicted isotope effects for several possible transition states and found that the experimentally measured isotope effects closely matched the ones predicted for a structure in which a proton is transferred from a catalytic-site aspartate to the proline leaving group of the substrate. They noted that the kinetic isotope effects were nearly identical for the normal and mutant proteases. This observation suggests that drug resistance arises from something other than transition-state interactions, the team says. They propose that a stable mimic of the transition structure would be a likely inhibitor against all biologically relevant HIV-1 protease variants.

 
Chemical & Engineering News
ISSN 0009-2347
Copyright © American Chemical Society

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