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Molecules 2016, 21(11), 1458; doi:10.3390/molecules21111458

Developing HIV-1 Protease Inhibitors through Stereospecific Reactions in Protein Crystals

1
Centre of Excellence in Biocrystallography, Department of Chemical and Pharmaceutical Sciences, University of Trieste, Trieste 34127, Italy
2
Department of Biochemistry, School of Sciences, Federal University of Technology Akure, P.M.B. 704, Akure 340252, Ondo State, Nigeria
3
Elettra-Sincrotrone Trieste, S.S. 14 Km 163.5 in Area Science Park, Basovizza, Trieste 34149, Italy
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Academic Editor: Josef Jampilek
Received: 26 September 2016 / Revised: 26 October 2016 / Accepted: 26 October 2016 / Published: 31 October 2016
View Full-Text   |   Download PDF [1816 KB, uploaded 31 October 2016]   |  

Abstract

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. View Full-Text
Keywords: HIV-1 protease; epoxide-based inhibitor; reactions in crystals; X-ray crystallography; stereospecific inhibitors HIV-1 protease; epoxide-based inhibitor; reactions in crystals; X-ray crystallography; stereospecific inhibitors
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Olajuyigbe, F.M.; Demitri, N.; De Zorzi, R.; Geremia, S. Developing HIV-1 Protease Inhibitors through Stereospecific Reactions in Protein Crystals. Molecules 2016, 21, 1458.

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