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

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 <i>Plasmodium falciparum</i> protein kinase <i>Pf</i>CLK3, which we used in combination with chemogenetics to validate <i>Pf</i>CLK3 as a drug target acting at multiple parasite life stages. Consistent with a role for <i>Pf</i>CLK3 in RNA splicing, inhibition resulted in the down-regulation of more than 400 essential parasite genes. Inhibition of <i>Pf</i>CLK3 mediated rapid killing of asexual liver- and blood-stage <i>P. falciparum</i> and blockade of gametocyte development, thereby preventing transmission, and also showed parasiticidal activity against <i>P. berghei</i> and <i>P. knowlesi</i> Hence, our data establish <i>Pf</i>CLK3 as a target for drugs, with the potential to offer a cure-to be prophylactic and transmission blocking in malaria.