Validation of the protein kinase PfCLK3 as a multistage cross-species malarial drug target.
Alam MM., Sanchez-Azqueta A., Janha O., Flannery EL., Mahindra A., Mapesa K., Char AB., Sriranganadane D., Brancucci NMB., Antonova-Koch Y., Crouch K., Simwela NV., Millar SB., Akinwale J., Mitcheson D., Solyakov L., Dudek K., Jones C., Zapatero C., Doerig C., Nwakanma DC., Vázquez MJ., Colmenarejo G., Lafuente-Monasterio MJ., Leon ML., Godoi PHC., Elkins JM., Waters AP., Jamieson AG., Álvaro EF., Ranford-Cartwright LC., Marti M., Winzeler EA., Gamo FJ., Tobin AB.
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.