Advanced search
Start date
Betweenand
Related content
(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

Full text
Author(s):
Show less -
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]
Total Authors: 35
Affiliation:
Show less -
[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
Total Affiliations: 15
Document type: Journal article
Source: Science; v. 365, n. 6456, p. 884+, AUG 30 2019.
Web of Science Citations: 2
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. (AU)

FAPESP's process: 13/50724-5 - Protein Kinase Chemical Biology Center: supporting drug development through open-access research
Grantee:Paulo Arruda
Support Opportunities: Research Grants - Research Partnership for Technological Innovation - PITE