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Structure based discovery of inhibitors of CYP125 and CYP142 from Mycobacterium tuberculosis

DOI: 10.1002/chem.202203868 DOI Help

Authors: Mona M. Katariya (University of Cambridge) , Matthew Snee (The University of Manchester) , Richard B. Tunnicliffe (The University of Manchester) , Madeline E. Kavanagh (The Scripps Research Institute) , Helena I. M. Boshoff (National Institute of Allergy and Infectious Diseases) , Cecilia N. Amadi (The University of Manchester) , Colin W. Levy (The University of Manchester) , Andrew W. Munro (The University of Manchester) , Chris Abell (University of Cambridge) , David Leys (The University of Manchester) , Anthony G. Coyne (University of Cambridge) , Kirsty J. Mclean (University of Huddersfield)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Chemistry – A European Journal

State: Published (Approved)
Published: March 2023
Diamond Proposal Number(s): 17773 , 24447

Open Access Open Access

Abstract: Mycobacterium tuberculosis (Mtb) was responsible for approximately 1.6 million deaths in 2021. With the emergence of extensive drug resistance, novel therapeutic agents are urgently needed, and continued drug discovery efforts required. Host-derived lipids such as cholesterol support Mtb growth, and are also suspected to function in immunomodulation, with links to persistence and immune evasion. Mtb cytochrome P450 (CYP) enzymes facilitate key steps in lipid catabolism and thus present potential targets for inhibition. Here we present a series of compounds based on an ethyl 5-(pyridin-4-yl)-1H-indole-2-carboxylate pharmacophore which bind strongly to both Mtb cholesterol oxidases CYP125 and CYP142. Using a structure-guided approach, combined with biophysical characterization, compounds with micromolar range in-cell activity against clinically relevant drug-resistant isolates were obtained. These will support further development of much-needed additional treatment options and provide routes to probe the role of CYP125 and CYP142 in Mtb pathogenesis.

Journal Keywords: ytochrome P450 enzymes; Drug design; Inhibitors; Structure-activity relationships; tuberculosis

Diamond Keywords: Tuberculosis (TB); Bacteria

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

Instruments: I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Added On: 15/03/2023 09:56

Chemistry A European J - 2023 - Katariya - Structure Based Discovery of Inhibitors of CYP125 and CYP142 from Mycobacterium.pdf

Discipline Tags:

Pathogens Infectious Diseases Health & Wellbeing Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)