A fragment-based approach to assess the ligandability of ArgB, ArgC, ArgD and ArgF in the L-arginine biosynthetic pathway of Mycobacterium tuberculosis
| Autor: | William R. Jacobs, Maria A. Pasillas, Ailidh Burgess, Tom L. Blundell, Sangeeta Tiwari, Anthony G. Coyne, James Cory-Wright, Vitor Mendes, Clio Meghir, Víctor Sebastián-Pérez, Sherine E. Thomas, Shaymaa A. Zaidan, Emma Cattermole, Pooja Gupta, Chris Abell |
|---|---|
| Přispěvatelé: | Bill & Melinda Gates Foundation, Gates Cambridge Scholarships, Wellcome Trust, National Institutes of Health (US), Thomas, Sherine E. [0000-0003-1152-4312], Sebastián-Pérez, Víctor [0000-0002-8248-4496], Burgess, Ailidh [0000-0002-9643-3163], Cattermole, Emma [0000-0002-0671-2207], Meghir, Clio [0000-0002-1551-6726], Abell, Chris [0000-0001-9174-1987], Coyne, Anthony G. [0000-0003-0205-5630], Jacobs Jr, William R. [0000-0003-3321-3080], Mendes, Vítor [0000-0002-2734-2444], Thomas, Sherine E., Sebastián-Pérez, Víctor, Burgess, Ailidh, Cattermole, Emma, Meghir, Clio, Abell, Chris, Coyne, Anthony G., Jacobs Jr, William R., Mendes, Vítor, Thomas, Sherine [0000-0003-1152-4312], Coyne, Anthony [0000-0003-0205-5630], Blundell, Tom [0000-0002-2708-8992], Apollo - University of Cambridge Repository |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
NMR
Nuclear magnetic resonance Tuberculosis Arginine TB tuberculosis Auxotrophy Biophysics Crystallographic data Biology Biochemistry Mycobacterium tuberculosis 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Biosynthesis Structural Biology Genetics medicine 030304 developmental biology ComputingMethodologies_COMPUTERGRAPHICS ASU asymmetric unit chemistry.chemical_classification 0303 health sciences Drug discovery ArgB ArgD ArgC ArgF medicine.disease biology.organism_classification Computer Science Applications FBDD Fragment-based drug discovery Enzyme chemistry DSF Differential scanning fluorimetry 030220 oncology & carcinogenesis FBDD ITC Isothermal titration calorimetry TP248.13-248.65 Research Article SPR Surface plasmon resonance Biotechnology |
| Zdroj: | Computational and Structural Biotechnology Journal, Vol 19, Iss, Pp 3491-3506 (2021) Digital.CSIC. Repositorio Institucional del CSIC instname Digital.CSIC: Repositorio Institucional del CSIC Consejo Superior de Investigaciones Científicas (CSIC) Computational and Structural Biotechnology Journal 'Computational and Structural Biotechnology Journal ', vol: 19, pages: 3491-3506 (2021) |
| ISSN: | 2001-0370 |
| Popis: | 16 p.-8 fig.-4 tab. 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. This work was funded by Bill and Melinda Gates Foundation HIT-TB (OPP1024021) and SHORTEN-TB (OPP1158806). PG was funded by a Gates Cambridge Scholarship. TLB is funded by the Wellcome Trust (Wellcome Trust Investigator Award 200814_Z_16_Z: RG83114). ST acknowledges SC1GM140968 grant from National Institute of Health to support this work. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|