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

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

  • Science. 2019 Aug 30;365(6456):eaau1682. doi: 10.1126/science.aau1682.
Mahmood M Alam 1,  Ana Sanchez-Azqueta 2,  Omar Janha 2,  Erika L Flannery 3,  Amit Mahindra 4,  Kopano Mapesa 4,  Aditya B Char 5,  Dev Sriranganadane 6,  Nicolas M B Brancucci 7,  Yevgeniya Antonova-Koch 8,  Kathryn Crouch 1,  Nelson Victor Simwela 1,  Scott B Millar 1,  Jude Akinwale 9,  Deborah Mitcheson 10,  Lev Solyakov 9,  Kate Dudek 9,  Carolyn Jones 9,  Cleofé Zapatero 11,  Christian Doerig 12,  Davis C Nwakanma 13,  Maria Jesús Vázquez 11,  Gonzalo Colmenarejo 14,  Maria Jose Lafuente-Monasterio 11,  Maria Luisa Leon 11,  Paulo H C Godoi 6,  Jon M Elkins 15,  Andrew P Waters 1,  Andrew G Jamieson 4,  Elena Fernández Álvaro 11,  Lisa C Ranford-Cartwright 5,  Matthias Marti 1,  Elizabeth A Winzeler 8,  Francisco Javier Gamo 11,  Andrew B Tobin 16
Affiliations

Affiliations

  • 1 Wellcome Centre for Integrative Parasitology, University of Glasgow, Glasgow G12 8QQ, UK.
  • 2 Centre for Translational Pharmacology, Institute of Molecular Cell and Systems Biology, University of Glasgow, Glasgow G12 8QQ, UK.
  • 3 Novartis Institute for Biomedical Research, Emeryville, CA 94608, USA.
  • 4 School of Chemistry, University of Glasgow, Glasgow G12 8QQ, UK.
  • 5 Institute of Biodiversity, Animal Health and Comparative Medicine, College of Medical, Veterinary and Life Science, University of Glasgow, Glasgow G12 8QQ, UK.
  • 6 Structural Genomics Consortium, Universidade Estadual de Campinas, Campinas, São Paulo 13083-886, Brazil.
  • 7 Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, 4051 Basel, Switzerland.
  • 8 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.
  • 9 Medical Research Council Toxicology Unit, University of Leicester, Leicester LE1 9HN, UK.
  • 10 Department of Molecular Cell Biology, University of Leicester, Leicester LE1 9HN, UK.
  • 11 Diseases of the Developing World, GlaxoSmithKline, 28760 Tres Cantos, Madrid, Spain.
  • 12 Biomedical Science Cluster, School of Health and Biomedical Sciences, Royal Melbourne Institute of Technology, Melbourne, VIC 3000, Australia.
  • 13 MRC Unit the Gambia, Fajara, Banjul, The Gambia.
  • 14 Biostatistics and Bioinformatics Unit, IMDEA Food Institute, 28049 Madrid, Spain.
  • 15 Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, UK.
  • 16 Centre for Translational Pharmacology, Institute of Molecular Cell and Systems Biology, University of Glasgow, Glasgow G12 8QQ, UK. [email protected].
PMID: 31467193 DOI: 10.1126/science.aau1682
Abstract

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 PfCLK3, which we used in combination with chemogenetics to validate PfCLK3 as a drug target acting at multiple Parasite life stages. Consistent with a role for PfCLK3 in RNA splicing, inhibition resulted in the down-regulation of more than 400 essential Parasite genes. Inhibition of PfCLK3 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 PfCLK3 as a target for drugs, with the potential to offer a cure-to be prophylactic and transmission blocking in malaria.

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