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

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Abstract

The requirement for next generation anti-malarials to be both curative and transmission blocking necessitate the identification of new druggable molecular pathways. Here we identify a selective inhibitor to the Plasmodium falciparum protein kinase PfCLK3 which we use 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 results in the down-regulation of >400 essential parasite genes. Inhibiting plasmodium CLK3 mediates rapid killing of asexual blood stage P. falciparum and blockade of gametocyte development preventing transmission, as well as showing parasiticidal activity against P. berghei and P. knowlesi. Hence, our data establishes PfCLK3 as a target with the potential to deliver both symptomatic treatment and transmission blocking in malaria