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
  • 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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