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

Journal article

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.

Authors: Alam, MM; Sanchez-Azqueta, A; Janha, O; Flannery, EL; Mahindra, A

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: American Association for the Advancement of Science
• Journal: Science
• Volume: 365
• Issue: 6456
• Article number: eaau1682
• Publication date: 2019-08-30
• Acceptance date: 2019-07-12
• DOI: 10.1126/science.aau1682
• EISSN: 1095-9203
• ISSN: 0036-8075
• Pmid: 31467193
• Language: English
• Keywords: FFR