Chemical tools for epichaperome-mediated interactome dysfunctions of the central nervous system.
Chemical tools for epichaperome-mediated interactome dysfunctions of the central nervous system.
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DOI：
10.1038/s41467-021-24821-2
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发表时间：
2021-08-03
影响因子：
16.6
通讯作者：
Chiosis G
中科院分区：
文献类型：
--
作者：
Bolaender A;Zatorska D;He H;Joshi S;Sharma S;Digwal CS;Patel HJ;Sun W;Imber BS;Ochiana SO;Patel MR;Shrestha L;Shah SK;Wang S;Karimov R;Tao H;Patel PD;Martin AR;Yan P;Panchal P;Almodovar J;Corben A;Rimner A;Ginsberg SD;Lyashchenko S;Burnazi E;Ku A;Kalidindi T;Lee SG;Grkovski M;Beattie BJ;Zanzonico P;Lewis JS;Larson S;Rodina A;Pillarsetty N;Tabar V;Dunphy MP;Taldone T;Shimizu F;Chiosis G
疾病是数千种蛋白质如何相互作用的表现。在几种疾病中，如癌症和阿尔茨海默病，蛋白质组范围内的蛋白质相互作用的紊乱是由被称为上壳体的分子伴侣支架的改变引起的。表没食子体定向的化学探针可用于检测和逆转有缺陷的伴侣体。在这里，我们提供了结构、生化和功能方面的见解，以发现外壳体探针，重点是它们在中枢神经系统疾病中的应用。我们在一项探索性的单组分配诊断研究(ClinicalTrials.gov标识符：NCT03371420)中展示了放射性标记的外壳体探针在细胞和小鼠中的靶向活性和动力学选择性，以及在人类患者中的原则证明。这项临床研究旨在确定接受单次微量放射性标记探针静脉注射的患者的药代动力学参数和不良事件发生率。综上所述，我们介绍了一个脑定向化学探针的发现平台，这些探针专门调节外周体，并在复杂生物系统中检测、量化和调节靶标方面提供了原理证明的应用。在这里，作者展示了对用于中枢神经系统疾病的外种皮定向化学探针的发现的结构、生化和功能的见解。从这项工作中产生的探测已经转化为人类对阿尔茨海默病和癌症的临床研究。
Diseases are a manifestation of how thousands of proteins interact. In several diseases, such as cancer and Alzheimer’s disease, proteome-wide disturbances in protein-protein interactions are caused by alterations to chaperome scaffolds termed epichaperomes. Epichaperome-directed chemical probes may be useful for detecting and reversing defective chaperomes. Here we provide structural, biochemical, and functional insights into the discovery of epichaperome probes, with a focus on their use in central nervous system diseases. We demonstrate on-target activity and kinetic selectivity of a radiolabeled epichaperome probe in both cells and mice, together with a proof-of-principle in human patients in an exploratory single group assignment diagnostic study (ClinicalTrials.gov Identifier: NCT03371420). The clinical study is designed to determine the pharmacokinetic parameters and the incidence of adverse events in patients receiving a single microdose of the radiolabeled probe administered by intravenous injection. In sum, we introduce a discovery platform for brain-directed chemical probes that specifically modulate epichaperomes and provide proof-of-principle applications in their use in the detection, quantification, and modulation of the target in complex biological systems. Here, the authors show structural, biochemical, and functional insights into the discovery of epichaperome‐ directed chemical probes for use in central nervous system diseases. Probes emerging from this work have translated to human clinical studies in Alzheimer’s disease and cancer.
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DOI：
10.1158/1078-0432.ccr-16-3151
发表时间：
2017-10-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Canella A;Welker AM;Yoo JY;Xu J;Abas FS;Kesanakurti D;Nagarajan P;Beattie CE;Sulman EP;Liu J;Gumin J;Lang FF;Gurcan MN;Kaur B;Sampath D;Puduvalli VK
通讯作者：
Puduvalli VK
影响因子：
3.5
作者：
Chiosis, G;Lucas, B;Rosen, N
通讯作者：
Rosen, N
影响因子：
4.6
作者：
Jhaveri, Komal L.;dos Anjos, Carlos H.;Modi, Shanu
通讯作者：
Modi, Shanu
影响因子：
64.5
作者：
Brennan CW;Verhaak RG;McKenna A;Campos B;Noushmehr H;Salama SR;Zheng S;Chakravarty D;Sanborn JZ;Berman SH;Beroukhim R;Bernard B;Wu CJ;Genovese G;Shmulevich I;Barnholtz-Sloan J;Zou L;Vegesna R;Shukla SA;Ciriello G;Yung WK;Zhang W;Sougnez C;Mikkelsen T;Aldape K;Bigner DD;Van Meir EG;Prados M;Sloan A;Black KL;Eschbacher J;Finocchiaro G;Friedman W;Andrews DW;Guha A;Iacocca M;O'Neill BP;Foltz G;Myers J;Weisenberger DJ;Penny R;Kucherlapati R;Perou CM;Hayes DN;Gibbs R;Marra M;Mills GB;Lander E;Spellman P;Wilson R;Sander C;Weinstein J;Meyerson M;Gabriel S;Laird PW;Haussler D;Getz G;Chin L;TCGA Research Network
通讯作者：
TCGA Research Network
DOI：
10.1038/s41568-018-0020-9
发表时间：
2018-09
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Joshi S;Wang T;Araujo TLS;Sharma S;Brodsky JL;Chiosis G
通讯作者：
Chiosis G