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| DOI | 10.1126/science.aau1682 |
| Validation of the protein kinase PfCLK3 as a multistage cross-species malarial drug target | |
| Alam, Mahmood M.1; Sanchez-Azqueta, Ana2; Janha, Omar2; Flannery, Erika L.3; Mahindra, Amit4; Mapesa, Kopano4; Char, Aditya B.5; Sriranganadane, Dev6; Brancucci, Nicolas M. B.7; Antonova-Koch, Yevgeniya8; Crouch, Kathryn1; Simwela, Nelson Victor1; Millar, Scott B.1; Akinwale, Jude9; Mitcheson, Deborah10; Solyakov, Lev9; Dudek, Kate9; Jones, Carolyn9; Zapatero, Cleofe11; Doerig, Christian12; Nwakanma, Davis C.13; Jesus Vazquez, Maria11; Colmenarejo, Gonzalo14; Jose Lafuente-Monasterio, Maria11; Luisa Leon, Maria11; Godoi, Paulo H. C.6; Elkins, Jon M.15; Waters, Andrew P.1; Jamieson, Andrew G.4; Fernandez Alvaro, Elena11; Ranford-Cartwright, Lisa C.5; Marti, Matthias1; Winzeler, Elizabeth A.8; Javier Gamo, Francisco11; Tobin, Andrew B.2 | |
| 2019-08-30 | |
| 发表期刊 | SCIENCE
 |
| ISSN | 0036-8075 |
| EISSN | 1095-9203 |
| 出版年 | 2019 |
| 卷号 | 365期号:6456页码:884-+ |
| 文章类型 | Article |
| 语种 | 英语 |
| 国家 | Scotland; USA; Brazil; Switzerland; England; Spain; Australia; Gambia |
| 英文摘要 | 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. |
| 领域 | 地球科学 ; 气候变化 ; 资源环境 |
| 收录类别 | SCI-E |
| WOS记录号 | WOS:000483975800038 |
| WOS关键词 | PLASMODIUM-FALCIPARUM MALARIA ; PRP4 KINASE ; TRI-SNRNP ; PARASITE ; RESISTANCE ; REVEALS ; DEUBIQUITINASE ; ARTEMISININ ; PIPERAQUINE ; INHIBITORS |
| WOS类目 | Multidisciplinary Sciences |
| WOS研究方向 | Science & Technology - Other Topics |
| 引用统计 | |
| 文献类型 | 期刊论文 |
| 条目标识符 | http://119.78.100.173/C666/handle/2XK7JSWQ/202200 |
| 专题 | 地球科学 资源环境科学 气候变化 |
| 作者单位 | 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 |
| 推荐引用方式 GB/T 7714 | Alam, Mahmood M.,Sanchez-Azqueta, Ana,Janha, Omar,et al. Validation of the protein kinase PfCLK3 as a multistage cross-species malarial drug target[J]. SCIENCE,2019,365(6456):884-+. |
| APA | Alam, Mahmood M..,Sanchez-Azqueta, Ana.,Janha, Omar.,Flannery, Erika L..,Mahindra, Amit.,...&Tobin, Andrew B..(2019).Validation of the protein kinase PfCLK3 as a multistage cross-species malarial drug target.SCIENCE,365(6456),884-+. |
| MLA | Alam, Mahmood M.,et al."Validation of the protein kinase PfCLK3 as a multistage cross-species malarial drug target".SCIENCE 365.6456(2019):884-+. |
| 条目包含的文件 | 条目无相关文件。 | |||||
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