Details

Autor(en) / Beteiligte

• Alam, Mahmood M
• Sanchez-Azqueta, Ana
• Janha, Omar
• Flannery, Erika L
• Mahindra, Amit
• Mapesa, Kopano
• Char, Aditya B
• Sriranganadane, Dev
• Brancucci, Nicolas M B
• Antonova-Koch, Yevgeniya
• Crouch, Kathryn
• Simwela, Nelson Victor
• Millar, Scott B
• Akinwale, Jude
• Mitcheson, Deborah
• Solyakov, Lev
• Dudek, Kate
• Jones, Carolyn
• Zapatero, Cleofé
• Doerig, Christian
• Nwakanma, Davis C
• Vázquez, Maria Jesús
• Colmenarejo, Gonzalo
• Lafuente-Monasterio, Maria Jose
• Leon, Maria Luisa
• Godoi, Paulo H C
• Elkins, Jon M
• Waters, Andrew P
• Jamieson, Andrew G
• Álvaro, Elena Fernández
• Ranford-Cartwright, Lisa C
• Marti, Matthias
• Winzeler, Elizabeth A
• Gamo, Francisco Javier
• Tobin, Andrew B

Titel

Validation of the protein kinase Pf CLK3 as a multistage cross-species malarial drug target

Ist Teil von

• Science (American Association for the Advancement of Science), 2019-08, Vol.365 (6456)

Ort / Verlag

United States

Erscheinungsjahr

2019

Quelle

American Association for the Advancement of Science

Beschreibungen/Notizen

• 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 protein kinase CLK3, which we used in combination with chemogenetics to validate CLK3 as a drug target acting at multiple parasite life stages. Consistent with a role for CLK3 in RNA splicing, inhibition resulted in the down-regulation of more than 400 essential parasite genes. Inhibition of CLK3 mediated rapid killing of asexual liver- and blood-stage and blockade of gametocyte development, thereby preventing transmission, and also showed parasiticidal activity against and Hence, our data establish CLK3 as a target for drugs, with the potential to offer a cure-to be prophylactic and transmission blocking in malaria.