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

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.

Source: ScienceNOW - August 28, 2019 Category: Science Authors: Alam, M. M., Sanchez-Azqueta, A., Janha, O., Flannery, E. L., Mahindra, A., Mapesa, K., Char, A. B., Sriranganadane, D., Brancucci, N. M. B., Antonova-Koch, Y., Crouch, K., Simwela, N. V., Millar, S. B., Akinwale, J., Mitcheson, D., Solyakov, L., Dudek, K Tags: Medicine, Diseases, Online Only r-articles Source Type: news