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

Author:

Alam Mahmood M.1ORCID,Sanchez-Azqueta Ana2ORCID,Janha Omar2ORCID,Flannery Erika L.3ORCID,Mahindra Amit4ORCID,Mapesa Kopano4,Char Aditya B.5ORCID,Sriranganadane Dev6ORCID,Brancucci Nicolas M. B.7ORCID,Antonova-Koch Yevgeniya8ORCID,Crouch Kathryn1ORCID,Simwela Nelson Victor1ORCID,Millar Scott B.1,Akinwale Jude9ORCID,Mitcheson Deborah10ORCID,Solyakov Lev9,Dudek Kate9,Jones Carolyn9ORCID,Zapatero Cleofé11,Doerig Christian12ORCID,Nwakanma Davis C.13ORCID,Vázquez Maria Jesús11,Colmenarejo Gonzalo14ORCID,Lafuente-Monasterio Maria Jose11ORCID,Leon Maria Luisa11ORCID,Godoi Paulo H. C.6ORCID,Elkins Jon M.15ORCID,Waters Andrew P.1ORCID,Jamieson Andrew G.4,Álvaro Elena Fernández11ORCID,Ranford-Cartwright Lisa C.5ORCID,Marti Matthias1ORCID,Winzeler Elizabeth A.8ORCID,Gamo Francisco Javier11ORCID,Tobin Andrew B.2ORCID

Affiliation:

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.

Abstract

Targeting parasite's protein kinase Malaria elimination goals are constantly eroded by the challenge of emerging drug and insecticide resistance. Alam et al. have taken established drug targets—CLK protein kinases involved in regulation of RNA splicing—and investigated how inhibition of the parasite's enzymes blocks completion of its complex life cycle. They identified an inhibitor of the parasite's CLK protein kinase that was 100-fold less active against the most closely related human protein kinase and effective at clearing rodent malaria parasites. Not only does this compound halt the development of sexual stages but it also limits transmission to the mosquito vector of the parasite, a key requirement for malaria drugs. Science , this issue p. eaau1682

Funder

National Institutes of Health

Medical Research Council

University Of Glasgow

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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