Developing HIV-1 Protease Inhibitors through Stereospecific Reactions in Protein Crystals.
Protease inhibitors are key components in the chemotherapy of HIV infection. However, the appearance of viral mutants routinely compromises their clinical efficacy, creating a constant need for new and more potent inhibitors. Recently, a new class of epoxide-based inhibitors of HIV-1 protease was investigated and the configuration of the epoxide carbons was demonstrated to play a crucial role in determining the binding affinity. Here we report the comparison between three crystal structures at near-atomic resolution of HIV-1 protease in complex with the epoxide-based inhibitor, revealing an in-situ epoxide ring opening triggered by a pH change in the mother solution of the crystal. Increased pH in the crystal allows a stereospecific nucleophile attack of an ammonia molecule onto an epoxide carbon, with formation of a new inhibitor containing amino-alcohol functions. The described experiments open a pathway for the development of new stereospecific protease inhibitors from a reactive lead compound.
Centre of Excellence in Biocrystallography, Department of Chemical and Pharmaceutical Sciences, University of Trieste, Trieste 34127, Italy. folajuyi@futa.edu.ng.|Department of Biochemistry, School of Sciences, Federal University of Technology Akure, P.M.B. 704, Akure 340252, Ondo State, Nigeria. folajuyi@futa.edu.ng.
Folasade M
FM
Olajuyigbe
Centre of Excellence in Biocrystallography, Department of Chemical and Pharmaceutical Sciences, University of Trieste, Trieste 34127, Italy. nicola.demitri@elettra.eu.|Elettra-Sincrotrone Trieste, S.S. 14 Km 163.5 in Area Science Park, Basovizza, Trieste 34149, Italy. nicola.demitri@elettra.eu.
Nicola
N
Demitri
Centre of Excellence in Biocrystallography, Department of Chemical and Pharmaceutical Sciences, University of Trieste, Trieste 34127, Italy. rdezorzi@units.it.
Rita
R
De Zorzi
Centre of Excellence in Biocrystallography, Department of Chemical and Pharmaceutical Sciences, University of Trieste, Trieste 34127, Italy. sgeremia@units.it.
Silvano
S
Geremia
D018360:Crystallography, X-Ray; D016333:HIV Protease / Q000737:chemistry*; D017320:HIV Protease Inhibitors / Q000737:chemistry*; D015497:HIV-1 / Q000201:enzymology*; D006863:Hydrogen-Ion Concentration; D062105:Molecular Docking Simulation
D017320:HIV Protease Inhibitors; D016333:HIV Protease
HIV-1 protease; X-ray crystallography; epoxide-based inhibitor; reactions in crystals; stereospecific inhibitors