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Science. 2019 Aug 30;365(6456). pii: eaau1682. doi: 10.1126/science.aau1682.

Validation of the protein kinase PfCLK3 as a multistage cross-species malarial drug target.

Author information

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. andrew.tobin@glasgow.ac.uk.

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.

PMID:
31467193
DOI:
10.1126/science.aau1682

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