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

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Alam, Mahmood M. ^[1] ; Sanchez-Azqueta, Ana ^[2] ; Janha, Omar ^[2] ; Flannery, Erika L. ^[3] ; Mahindra, Amit ^[4] ; Mapesa, Kopano ^[4] ; Char, Aditya B. ^[5] ; Sriranganadane, Dev ^[6] ; Brancucci, Nicolas M. B. ^[7] ; Antonova-Koch, Yevgeniya ^[8] ; Crouch, Kathryn ^[1] ; Simwela, Nelson Victor ^[1] ; Millar, Scott B. ^[1] ; Akinwale, Jude ^[9] ; Mitcheson, Deborah ^[10] ; Solyakov, Lev ^[9] ; Dudek, Kate ^[9] ; Jones, Carolyn ^[9] ; Zapatero, Cleofe ^[11] ; Doerig, Christian ^[12] ; Nwakanma, Davis C. ^[13] ; Jesus Vazquez, Maria ^[11] ; Colmenarejo, Gonzalo ^[14] ; Jose Lafuente-Monasterio, Maria ^[11] ; Luisa Leon, Maria ^[11] ; Godoi, Paulo H. C. ^[6] ; Elkins, Jon M. ^[15] ; Waters, Andrew P. ^[1] ; Jamieson, Andrew G. ^[4] ; Fernandez Alvaro, Elena ^[11] ; Ranford-Cartwright, Lisa C. ^[5] ; Marti, Matthias ^[1] ; Winzeler, Elizabeth A. ^[8] ; Javier Gamo, Francisco ^[11] ; Tobin, Andrew B. ^[2]

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^[1] Univ Glasgow, Wellcome Ctr Integrat Parasitol, Glasgow G12 8QQ, Lanark - Scotland

^[2] Univ Glasgow, Ctr Translat Pharmacol, Inst Mol Cell & Syst Biol, Glasgow G12 8QQ, Lanark - Scotland

^[3] Novartis Inst Biomed Res, Emeryville, CA 94608 - USA

^[4] Univ Glasgow, Sch Chem, Glasgow G12 8QQ, Lanark - Scotland

^[5] Univ Glasgow, Coll Med Vet & Life Sci, Inst Biodivers Anim Hlth & Comparat Med, Glasgow G12 8QQ, Lanark - Scotland

^[6] Univ Estadual Campinas, Struct Genom Consortium, BR-13083886 Campinas, SP - Brazil

^[7] Swiss Trop & Publ Hlth Inst, Dept Med Parasitol & Infect Biol, CH-4051 Basel - Switzerland

^[8] Univ Calif San Diego, Sch Med, Skaggs Sch Pharmaceut Sci, UC Hlth Sci Ctr Immunol Infect & Inflammat, La Jolla, CA 92093 - USA

^[9] Univ Leicester, MRC, Toxicol Unit, Leicester LE1 9HN, Leics - England

^[10] Univ Leicester, Dept Mol Cell Biol, Leicester LE1 9HN, Leics - England

^[11] GlaxoSmithKline, Dis Dev World, Madrid 28760 - Spain

^[12] RMIT Univ, Sch Hlth & Biomed Sci, Biomed Sci Cluster, Melbourne, Vic 3000 - Australia

^[13] MRC Unit Gambia, Banjul - Gambia

^[14] IMDEA Food Inst, Biostat & Bioinformat Unit, Madrid 28049 - Spain

^[15] Univ Oxford, Nuffield Dept Clin Med, Struct Genom Consortium, Oxford OX3 7DQ - England

• Tipo de documento: Artigo Científico
• Fonte: Science; v. 365, n. 6456, p. 884+, AUG 30 2019.
• Citações Web of Science: 2

Resumo

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. (AU)

• Processo FAPESP: 13/50724-5 - Centro de Biologia Química de Proteínas Quinases: alavancando desenvolvimento de fármacos através de pesquisa de acesso aberto
• Beneficiário: Paulo Arruda
• Modalidade de apoio: Auxílio à Pesquisa - Parceria para Inovação Tecnológica - PITE