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

Alam, Mahmood M. and Sanchez-Azqueta, Ana and Janha, Omar and Flannery, Erika L. and Mahindra, Amit and Mapesa, Kopano and Char, Aditya B. and Sriranganadane, Dev and Brancucci, Nicolas M. B. and Antonova-Koch, Yevgeniya and Crouch, Kathryn and Simwela, Nelson Victor and Millar, Scott B. and Akinwale, Jude and Mitcheson, Deborah and Solyakov, Lev and Dudek, Kate and Jones, Carolyn and Zapatero, Cleofé and Doerig, Christian and Nwakanma, Davis C. and Vázquez, Maria Jesús and Colmenarejo, Gonzalo and Lafuente-Monasterio, Maria Jose and Leon, Maria Luisa and Godoi, Paulo H. C. and Elkins, Jon M. and Waters, Andrew P. and Jamieson, Andrew G. and Álvaro, Elena Fernández and Ranford-Cartwright, Lisa C. and Marti, Matthias and Winzeler, Elizabeth A. and Gamo, Francisco Javier and Tobin, Andrew B.. (2019) Validation of the protein kinase PfCLK3 as a multistage cross-species malarial drug target. Science, 365 (6456). eaau1682.

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Official URL: https://edoc.unibas.ch/71942/

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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; Pf; CLK3, which we used in combination with chemogenetics to validate; Pf; CLK3 as a drug target acting at multiple parasite life stages. Consistent with a role for; Pf; CLK3 in RNA splicing, inhibition resulted in the down-regulation of more than 400 essential parasite genes. Inhibition of; Pf; CLK3 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; Pf; CLK3 as a target for drugs, with the potential to offer a cure-to be prophylactic and transmission blocking in malaria.

Faculties and Departments:	09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) 09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology (MPI) > Helminth Drug Development (Keiser)
UniBasel Contributors:	Brancucci, Nicolas
Item Type:	Article, refereed
Article Subtype:	Research Article
Publisher:	American Association for the Advancement of Science
ISSN:	0036-8075
e-ISSN:	1095-9203
Note:	Publication type according to Uni Basel Research Database: Journal article
Identification Number:	doi: 10.1126/science.aau1682 pmid: 31467193
Last Modified:	17 Sep 2019 12:27
Deposited On:	17 Sep 2019 12:27

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