Validation of the protein kinase Pf CLK3 as a multistage cross-species malarial drug target.

Autor: Alam MM; Wellcome Centre for Integrative Parasitology, University of Glasgow, Glasgow G12 8QQ, UK., Sanchez-Azqueta A; Centre for Translational Pharmacology, Institute of Molecular Cell and Systems Biology, University of Glasgow, Glasgow G12 8QQ, UK., Janha O; Centre for Translational Pharmacology, Institute of Molecular Cell and Systems Biology, University of Glasgow, Glasgow G12 8QQ, UK., Flannery EL; Novartis Institute for Biomedical Research, Emeryville, CA 94608, USA., Mahindra A; School of Chemistry, University of Glasgow, Glasgow G12 8QQ, UK., Mapesa K; School of Chemistry, University of Glasgow, Glasgow G12 8QQ, UK., Char AB; Institute of Biodiversity, Animal Health and Comparative Medicine, College of Medical, Veterinary and Life Science, University of Glasgow, Glasgow G12 8QQ, UK., Sriranganadane D; Structural Genomics Consortium, Universidade Estadual de Campinas, Campinas, São Paulo 13083-886, Brazil., Brancucci NMB; Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, 4051 Basel, Switzerland., Antonova-Koch Y; Skaggs School of Pharmaceutical Sciences, UC Health Sciences Center for Immunology, Infection and Inflammation, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA., Crouch K; Wellcome Centre for Integrative Parasitology, University of Glasgow, Glasgow G12 8QQ, UK., Simwela NV; Wellcome Centre for Integrative Parasitology, University of Glasgow, Glasgow G12 8QQ, UK., Millar SB; Wellcome Centre for Integrative Parasitology, University of Glasgow, Glasgow G12 8QQ, UK., Akinwale J; Medical Research Council Toxicology Unit, University of Leicester, Leicester LE1 9HN, UK., Mitcheson D; Department of Molecular Cell Biology, University of Leicester, Leicester LE1 9HN, UK., Solyakov L; Medical Research Council Toxicology Unit, University of Leicester, Leicester LE1 9HN, UK., Dudek K; Medical Research Council Toxicology Unit, University of Leicester, Leicester LE1 9HN, UK., Jones C; Medical Research Council Toxicology Unit, University of Leicester, Leicester LE1 9HN, UK., Zapatero C; Diseases of the Developing World, GlaxoSmithKline, 28760 Tres Cantos, Madrid, Spain., Doerig C; Biomedical Science Cluster, School of Health and Biomedical Sciences, Royal Melbourne Institute of Technology, Melbourne, VIC 3000, Australia., Nwakanma DC; MRC Unit the Gambia, Fajara, Banjul, The Gambia., Vázquez MJ; Diseases of the Developing World, GlaxoSmithKline, 28760 Tres Cantos, Madrid, Spain., Colmenarejo G; Biostatistics and Bioinformatics Unit, IMDEA Food Institute, 28049 Madrid, Spain., Lafuente-Monasterio MJ; Diseases of the Developing World, GlaxoSmithKline, 28760 Tres Cantos, Madrid, Spain., Leon ML; Diseases of the Developing World, GlaxoSmithKline, 28760 Tres Cantos, Madrid, Spain., Godoi PHC; Structural Genomics Consortium, Universidade Estadual de Campinas, Campinas, São Paulo 13083-886, Brazil., Elkins JM; Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, UK., Waters AP; Wellcome Centre for Integrative Parasitology, University of Glasgow, Glasgow G12 8QQ, UK., Jamieson AG; School of Chemistry, University of Glasgow, Glasgow G12 8QQ, UK., Álvaro EF; Diseases of the Developing World, GlaxoSmithKline, 28760 Tres Cantos, Madrid, Spain., Ranford-Cartwright LC; Institute of Biodiversity, Animal Health and Comparative Medicine, College of Medical, Veterinary and Life Science, University of Glasgow, Glasgow G12 8QQ, UK., Marti M; Wellcome Centre for Integrative Parasitology, University of Glasgow, Glasgow G12 8QQ, UK., Winzeler EA; Skaggs School of Pharmaceutical Sciences, UC Health Sciences Center for Immunology, Infection and Inflammation, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA., Gamo FJ; Diseases of the Developing World, GlaxoSmithKline, 28760 Tres Cantos, Madrid, Spain., Tobin AB; Centre for Translational Pharmacology, Institute of Molecular Cell and Systems Biology, University of Glasgow, Glasgow G12 8QQ, UK. andrew.tobin@glasgow.ac.uk.
Jazyk: angličtina
Zdroj: Science (New York, N.Y.) [Science] 2019 Aug 30; Vol. 365 (6456).
DOI: 10.1126/science.aau1682
Abstrakt: The requirement for next-generation antimalarials to be both curative and transmission-blocking necessitates the identification of previously undiscovered druggable molecular pathways. We identified a selective inhibitor of the Plasmodium falciparum protein kinase Pf CLK3, which we used in combination with chemogenetics to validate Pf CLK3 as a drug target acting at multiple parasite life stages. Consistent with a role for Pf CLK3 in RNA splicing, inhibition resulted in the down-regulation of more than 400 essential parasite genes. Inhibition of Pf CLK3 mediated rapid killing of asexual liver- and blood-stage P. falciparum and blockade of gametocyte development, thereby preventing transmission, and also showed parasiticidal activity against P. berghei and P. knowlesi Hence, our data establish Pf CLK3 as a target for drugs, with the potential to offer a cure-to be prophylactic and transmission blocking in malaria.
(Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
Databáze: MEDLINE
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