Chemical interrogation of the malaria kinome.
Chemical interrogation of the malaria kinome.
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DOI：
10.1002/cbic.201400025
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发表时间：
2014-09-05
期刊：
影响因子：
3.2
通讯作者：
Clardy, Jon
中科院分区：
文献类型：
--
作者：
Derbyshire, Emily R.;Zuzarte-Luis, Vanessa;Magalhaes, Andreia D.;Kato, Nobutaka;Sanschagrin, Paul C.;Wang, Jinhua;Zhou, Wenjun;Miduturu, Chandrasekhar V.;Mazitschek, Ralph;Sliz, Piotr;Mota, Maria M.;Gray, Nathanael S.;Clardy, Jon
疟疾是一种由疟原虫属真核寄生虫引起的传染病，每年折磨着数亿人。寄生虫和它的宿主都利用蛋白激酶来调节基本的细胞过程。寄生虫基因组的生物信息学分析预测了至少65种蛋白激酶，但它们的生物学功能和治疗潜力在很大程度上是未知的。我们分析了1358个小分子激酶抑制剂，以评估人类和疟疾激酶在疟原虫感染肝细胞中的作用，肝细胞是寄生虫在症状性血液阶段之前的强制性但短暂的发育阶段。该筛选确定了几种抑制肝细胞中寄生虫负荷的小分子，其中一些具有纳摩尔的功效，并且随后评估了每种化合物对血期疟疾的活性。大多数筛选命中抑制肝脏和血液阶段的疟疾寄生虫，它们具有不同的基因表达谱并感染不同的宿主细胞。对文库成员现有激酶活性分析数据的评估表明，几种激酶对疟疾寄生虫至关重要，包括周期蛋白依赖性激酶、糖原合成酶激酶和磷酸肌醇-3激酶。CDK抑制剂被发现与疟原虫蛋白激酶5结合，但这些化合物可能针对多种寄生虫激酶。所鉴定的激酶抑制剂的双阶段抑制使它们成为有用的化学探针和抗疟疾发展的有希望的起点。
Malaria, an infectious disease caused by eukaryotic parasites from the genus Plasmodium, afflicts hundreds of millions of people every year. Both the parasite and its host utilize protein kinases to regulate essential cellular processes. Bioinformatic analyses of parasite genomes predict at least 65 protein kinases, but their biological functions and therapeutic potential are largely unknown. We profiled 1,358 small molecule kinase inhibitors to evaluate the role of both the human and malaria kinomes in Plasmodium infection of liver cells, the parasites’ obligatory but transient developmental stage that precedes the symptomatic blood stage. The screen identified several small molecules that inhibit parasite load in liver cells, some with nanomolar efficacy, and each compound was subsequently assessed for activity against blood stage malaria. Most of the screening hits inhibited both liver and blood stage malaria parasites, which have dissimilar gene expression profiles and infect different host cells. Evaluation of existing kinase activity profiling data for the library members suggests several kinases are essential to malaria parasites, including cyclin-dependent kinases, glycogen synthase kinases, and phosphoinositide-3-kinases. CDK inhibitors were found to bind to Plasmodium protein kinase 5, but it is likely that these compounds target multiple parasite kinases. The dual stage inhibition of the identified kinase inhibitors makes them useful chemical probes and promising starting points for antimalarial development.
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DOI：
10.1038/nrmicro3138
发表时间：
2013-12
期刊：
Nature reviews. Microbiology
影响因子：
--
作者：
通讯作者：
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影响因子：
7.3
作者：
Fugel, Wiebke;Oberholzer, Anselm Erich;Kunick, Conrad
通讯作者：
Kunick, Conrad
影响因子：
7.3
作者：
Gujjar R;El Mazouni F;White KL;White J;Creason S;Shackleford DM;Deng X;Charman WN;Bathurst I;Burrows J;Floyd DM;Matthews D;Buckner FS;Charman SA;Phillips MA;Rathod PK
通讯作者：
Rathod PK
影响因子：
14.8
作者：
Knapp, Stefan;Arruda, Paulo;Zuercher, William J.
通讯作者：
Zuercher, William J.
影响因子：
2.7
作者：
Emmitte, Kyle A.;Adjebang, George M.;Cheung, Mui
通讯作者：
Cheung, Mui