Lysyl-tRNA synthetase, a target for urgently needed M. tuberculosis drugs.

Autor: Green SR; Drug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK., Davis SH; Drug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK., Damerow S; Drug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK., Engelhart CA; Dept. of Microbiology and Immunology, Weill Cornell Medical College, New York, NY, USA., Mathieson M; Drug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK., Baragaña B; Drug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK., Robinson DA; Drug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK., Tamjar J; Drug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK., Dawson A; Drug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK., Tamaki FK; Drug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK., Buchanan KI; Drug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK., Post J; Drug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK., Dowers K; Drug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK., Shepherd SM; Drug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK., Jansen C; Drug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK., Zuccotto F; Drug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK., Gilbert IH; Drug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK., Epemolu O; Drug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK., Riley J; Drug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK., Stojanovski L; Drug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK., Osuna-Cabello M; Drug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK., Pérez-Herrán E; Global Health Medicines R&D, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, 28760, Madrid, Spain., Rebollo MJ; Global Health Medicines R&D, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, 28760, Madrid, Spain., Guijarro López L; Global Health Medicines R&D, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, 28760, Madrid, Spain., Casado Castro P; Global Health Medicines R&D, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, 28760, Madrid, Spain., Camino I; Global Health Medicines R&D, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, 28760, Madrid, Spain., Kim HC; Dept. of Microbiology and Immunology, Weill Cornell Medical College, New York, NY, USA., Bean JM; Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, USA., Nahiyaan N; Dept. of Microbiology and Immunology, Weill Cornell Medical College, New York, NY, USA., Rhee KY; Dept. of Microbiology and Immunology, Weill Cornell Medical College, New York, NY, USA., Wang Q; Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, 9000 Rockville Pike, Bethesda, MD, USA., Tan VY; Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, 9000 Rockville Pike, Bethesda, MD, USA., Boshoff HIM; Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, 9000 Rockville Pike, Bethesda, MD, USA., Converse PJ; Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD, USA., Li SY; Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD, USA., Chang YS; Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD, USA., Fotouhi N; Global Alliance for TB Drug Development, New York, NY, USA., Upton AM; Global Alliance for TB Drug Development, New York, NY, USA., Nuermberger EL; Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD, USA., Schnappinger D; Dept. of Microbiology and Immunology, Weill Cornell Medical College, New York, NY, USA., Read KD; Drug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK., Encinas L; Global Health Medicines R&D, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, 28760, Madrid, Spain., Bates RH; Global Health Medicines R&D, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, 28760, Madrid, Spain., Wyatt PG; Drug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK., Cleghorn LAT; Drug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK. l.a.t.cleghorn@dundee.ac.uk.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 Oct 11; Vol. 13 (1), pp. 5992. Date of Electronic Publication: 2022 Oct 11.
DOI: 10.1038/s41467-022-33736-5
Abstrakt: Tuberculosis is a major global cause of both mortality and financial burden mainly in low and middle-income countries. Given the significant and ongoing rise of drug-resistant strains of Mycobacterium tuberculosis within the clinical setting, there is an urgent need for the development of new, safe and effective treatments. Here the development of a drug-like series based on a fused dihydropyrrolidino-pyrimidine scaffold is described. The series has been developed against M. tuberculosis lysyl-tRNA synthetase (LysRS) and cellular studies support this mechanism of action. DDD02049209, the lead compound, is efficacious in mouse models of acute and chronic tuberculosis and has suitable physicochemical, pharmacokinetic properties and an in vitro safety profile that supports further development. Importantly, preliminary analysis using clinical resistant strains shows no pre-existing clinical resistance towards this scaffold.
(© 2022. The Author(s).)
Databáze: MEDLINE
Externí odkaz: