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Determinants of the Inhibition of DprE1 and CYP2C9 by Antitubercular Thiophenes

DOI: 10.1002/anie.201707324 DOI Help

Authors: Renhe Liu (California Institute for Biomedical Research (Calibr)) , Xiaoxuan Lyu (California Institute for Biomedical Research (Calibr)) , Mei-hui Hsu (The Scripps Research Institute) , Catherine Vilcheze (Howard Hughes Medical Institute, Albert Einstein College of Medicine) , Scott G. Franzblau (Institute for Tuberculosis Research, University of Illinois) , William R. Jacobs (Howard Hughes Medical Institute, Albert Einstein College of Medicine) , Gurdyal S. Besra (University of Birmingham) , Eric F. Johnson (The Scripps Research Institute) , Klaus Futterer (University of Birmingham) , Feng Wang (California Institute for Biomedical Research (Calibr))
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Angewandte Chemie International Edition

State: Published (Approved)
Published: August 2017
Diamond Proposal Number(s): 8359

Abstract: Mycobacterium tuberculosis (Mtb) DprE1, an essential isomerase for the biosynthesis of the mycobacterial cell wall, is a validated target for tuberculosis (TB) drug development. Here we report the X-ray crystal structures of DprE1 and the DprE1 resistant mutant (Y314C) in complexes with TCA1 derivatives to elucidate the molecular basis of their inhibitory activities and an unconventional resistance mechanism, which enabled us to optimize the potency of the analogs. The selected lead compound showed excellent in vitro and in vivo activities, and low risk of toxicity profile except for the inhibition of CYP2C9. A crystal structure of CYP2C9 in complex with a TCA1 analog revealed the similar interaction patterns to the DprE1-TCA1 complex. Guided by the structures, an optimized molecule was generated with differential inhibitory activities against DprE1 and CYP2C9, which provides insights for development of a clinical candidate to treat TB.

Journal Keywords: DprE1; CYP2C9; anti-tubercular drugs; drug-drug interactions; drug development

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


Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography