| Literature DB >> 31467193 |
Mahmood M Alam1, Ana Sanchez-Azqueta2, Omar Janha2, Erika L Flannery3, Amit Mahindra4, Kopano Mapesa4, Aditya B Char5, Dev Sriranganadane6, Nicolas M B Brancucci7, Yevgeniya Antonova-Koch8, Kathryn Crouch1, Nelson Victor Simwela1, Scott B Millar1, Jude Akinwale9, Deborah Mitcheson10, Lev Solyakov9, Kate Dudek9, Carolyn Jones9, Cleofé Zapatero11, Christian Doerig12, Davis C Nwakanma13, Maria Jesús Vázquez11, Gonzalo Colmenarejo14, Maria Jose Lafuente-Monasterio11, Maria Luisa Leon11, Paulo H C Godoi6, Jon M Elkins15, Andrew P Waters1, Andrew G Jamieson4, Elena Fernández Álvaro11, Lisa C Ranford-Cartwright5, Matthias Marti1, Elizabeth A Winzeler8, Francisco Javier Gamo11, Andrew B Tobin16.
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 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.Entities:
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Year: 2019 PMID： 31467193 DOI： 10.1126/science.aau1682
Source DB: PubMed Journal: Science ISSN： 0036-8075 Impact factor: 47.728