3TOH

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

(2016) Molecules 21

• PubMed: 27809253 Search on PubMedSearch on PubMed Central
• DOI: https://doi.org/10.3390/molecules21111458
• Primary Citation of Related Structures:  
  3TOF, 3TOG, 3TOH


• PubMed 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.

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Organizational Affiliation: 

Centre of Excellence in Biocrystallography, Department of Chemical and Pharmaceutical Sciences, University of Trieste, Trieste 34127, Italy. [email protected].