Validation of the protein kinase PfCLK3 as a multistage cross-species malarial drug target.
Mahmood M AlamAna Sanchez-AzquetaOmar JanhaErika L FlanneryAmit MahindraKopano MapesaAditya B CharDev SriranganadaneNicolas M B BrancucciYevgeniya Antonova-KochKathryn CrouchNelson Victor SimwelaScott B MillarJude AkinwaleDeborah MitchesonLev SolyakovKate DudekCarolyn JonesCleofé ZapateroChristian DoerigDavis C NwakanmaMaria Jesús VázquezGonzalo ColmenarejoMaria Jose Lafuente-MonasterioMaria Luisa LeonPaulo H C GodoiJonathan M ElkinsAndrew P WatersAndrew G JamiesonElena Fernández ÁlvaroLisa C Ranford-CartwrightMatthias MartiElizabeth A WinzelerFrancisco Javier GamoAndrew B TobinPublished in: Science (New York, N.Y.) (2020)
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.