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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.

Original publication

DOI

10.1126/science.aau1682

Type

Journal article

Journal

Science (New York, N.Y.)

Publication Date

08/2019

Volume

365

Addresses

Wellcome Centre for Integrative Parasitology, University of Glasgow, Glasgow G12 8QQ, UK.

Keywords

Animals, Mice, Inbred BALB C, Mice, Plasmodium falciparum, Protein-Serine-Threonine Kinases, Protozoan Proteins, Protein Kinase Inhibitors, Antimalarials, Gametogenesis, RNA Splicing, Protein-Tyrosine Kinases, Small Molecule Libraries, High-Throughput Screening Assays, Molecular Targeted Therapy