A fragment-based approach to assess the ligandability of ArgB, ArgC, ArgD and ArgF in the L-arginine biosynthetic pathway of Mycobacterium tuberculosis

DOI: 10.1016/j.csbj.2021.06.006

Authors: Pooja Gupta (University of Cambridge) , Sherine E. Thomas (University of Cambridge) , Shaymaa A. Zaidan (University of Texas at El Paso) , Maria A. Pasillas (University of Texas at El Paso) , James Cory-Wright (University of Cambridge) , Víctor Sebastián-Pérez (University of Cambridge; Centro de Investigaciones Biológicas Margarita Salas (CSIC)) , Ailidh Burgess (University of Cambridge) , Emma Cattermole (University of Cambridge) , Clio Meghir (University of Cambridge) , Chris Abell (University of Cambridge) , Anthony G. Coyne (University of Cambridge) , William R. Jacobs (Albert Einstein College of Medicine) , Tom L. Blundell (University of Cambridge) , Sangeeta Tiwari (University of Texas at El Paso) , Vitor Mendes (University of Cambridge)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Computational And Structural Biotechnology Journal , VOL 19 , PAGES 3491 - 3506

State: Published (Approved)
Published: June 2021
Diamond Proposal Number(s): 14043 , 18548

Abstract: The L-arginine biosynthesis pathway consists of eight enzymes that catalyse the conversion of L-glutamate to L-arginine. Arginine auxotrophs (argB/argF deletion mutants) of Mycobacterium tuberculosis are rapidly sterilised in mice, while inhibition of ArgJ with Pranlukast was found to clear chronic M. tuberculosis infection in a mouse model. Enzymes in the arginine biosynthetic pathway have therefore emerged as promising targets for anti-tuberculosis drug discovery. In this work, the ligandability of four enzymes of the pathway ArgB, ArgC, ArgD and ArgF is assessed using a fragment-based approach. We identify several hits against these enzymes validated with biochemical and biophysical assays, as well as X-ray crystallographic data, which in the case of ArgB were further confirmed to have on-target activity against M. tuberculosis. These results demonstrate the potential for more enzymes in this pathway to be targeted with dedicated drug discovery programmes.

Journal Keywords: ArgB; ArgC; ArgD; ArgF; Mycobacterium tuberculosis; FBDD

Diamond Keywords: Tuberculosis (TB); Bacteria; Enzymes

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


Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Other Facilities: id30B at ESRF

Added On: 30/06/2021 09:46

Documents:
1-s2.0-S2001037021002373-main.pdf

Discipline Tags:

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

Technical Tags:

Diffraction Macromolecular Crystallography (MX)