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A selective PPM1A inhibitor activates autophagy to restrict the survival of Mycobacterium tuberculosis

文献类型：期刊论文

作者Berton, Stefania5; Chen, Lu3,4; Liang, Yi Chu5; Xu, Zhongliang3,4; Afriyie-Asante, Afrakoma5; Rajabalee, Nusrah5; Yang, Weibo2,3,4; Sun, Jim1,5
刊名CELL CHEMICAL BIOLOGY
出版日期2022-07-21
卷号29期号:7页码:1126-+
ISSN号2451-9456
DOI10.1016/j.chembiol.2022.03.006
通讯作者Yang, Weibo(yweibo@simm.ac.cn) ; Sun, Jim(jim.sun@uottawa.ca)
英文摘要Metal-dependent protein phosphatases (PPMs) have essential roles in a variety of cellular processes, including inflammation, proliferation, differentiation, and stress responses, which are intensively investigated in cancer and metabolic diseases. Targeting PPMs to modulate host immunity in response to pathogens is an ambitious proposition. The feasibility of such a strategy is unproven because development of inhibitors against PPMs is challenging and suffers from poor selectivity. Combining a biomimetic modularization strategy with function-oriented synthesis, we design, synthesize and screen more than 500 pseudo-natural products, resulting in the discovery of a potent, selective, and non-cytotoxic small molecule inhibitor for PPM1A, SMIP-30. Inhibition of PPM1A with SMIP-30 or its genetic ablation (Delta PPM1A) activated autophagy through a mechanism dependent on phosphorylation of p62-SQSTM1, which restricted the intracellular survival of Mycobacterium tuberculosis in macrophages and in the lungs of infected mice. SMIP-30 provides proof of concept that PPMs are druggable and promising targets for the development of host-directed therapies against tuberculosis.
WOS关键词PROTEIN PHOSPHATASE ; IN-VITRO ; MACROPHAGES ; PHOSPHORYLATION ; MECHANISM ; DEFENSE
WOS研究方向Biochemistry & Molecular Biology
语种英语
出版者CELL PRESS
WOS记录号WOS:000842038100005
源URL[http://119.78.100.183/handle/2S10ELR8/302299]  
专题中国科学院上海药物研究所
通讯作者Yang, Weibo; Sun, Jim
作者单位1.Univ Ottawa, Ctr Infect Immun & Inflammat, Ottawa, ON K1H 8M5, Canada
2.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med SIMM, Chinese Acad Sci Key Lab Receptor Res, Shanghai 201203, Peoples R China
5.Univ Ottawa, Dept Biochem Microbiol & Immunol, Ottawa, ON K1H 8M5, Canada
推荐引用方式
GB/T 7714		 Berton, Stefania,Chen, Lu,Liang, Yi Chu,et al. A selective PPM1A inhibitor activates autophagy to restrict the survival of Mycobacterium tuberculosis[J]. CELL CHEMICAL BIOLOGY,2022,29(7):1126-+.
APA Berton, Stefania.,Chen, Lu.,Liang, Yi Chu.,Xu, Zhongliang.,Afriyie-Asante, Afrakoma.,...&Sun, Jim.(2022).A selective PPM1A inhibitor activates autophagy to restrict the survival of Mycobacterium tuberculosis.CELL CHEMICAL BIOLOGY,29(7),1126-+.
MLA Berton, Stefania,et al."A selective PPM1A inhibitor activates autophagy to restrict the survival of Mycobacterium tuberculosis".CELL CHEMICAL BIOLOGY 29.7(2022):1126-+.

入库方式： OAI收割

来源：上海药物研究所

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