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Small molecule targeting CELF1 RNA-binding activity to control HSC activation and liver fibrosis

文献类型：期刊论文

作者Tan, Yang2; Sun, Xueqing2; Xu, Yizhu2; Tang, Bingjie2; Xu, Shuaiqi2; Lu, Dong3; Ye, Yan3; Luo, Xiaomin3,4; Diao, Xu5; Li, Fulong6
刊名NUCLEIC ACIDS RESEARCH
出版日期2022-03-02
页码12
ISSN号0305-1048
DOI10.1093/nar/gkac139
通讯作者Xu, Qiang(molpharm@163.com) ; Wu, Xingxin(xingxin.wu@nju.edu.cn)
英文摘要CUGBP Elav-like family member 1 (CELF1), an RNA-binding protein (RBP), plays important roles in the pathogenesis of diseases such as myotonic dystrophy, liver fibrosis and cancers. However, targeting CELF1 is still a challenge, as RBPs are considered largely undruggable. Here, we discovered that compound 27 disrupted CELF1-RNA binding via structure-based virtual screening and biochemical assays. Compound 27 binds directly to CELF1 and competes with RNA for binding to CELF1. Compound 27 promotes IFN-gamma secretion and suppresses TGF-beta 1-induced hepatic stellate cell (HSC) activation by inhibiting CELF1-mediated IFN-gamma mRNA decay. In vivo, compound 27 attenuates CCl4-induced murine liver fibrosis. Furthermore, the structure-activity relationship analysis was performed and compound 841, a derivative of compound 27, was identified as a selective CELF1 inhibitor. In conclusion, targeting CELF1 RNA-binding activity with small molecules was achieved, which provides a novel strategy for treating liver fibrosis and other CELF1-mediated diseases.
WOS关键词GU-RICH ELEMENTS ; STRUCTURAL INSIGHTS ; STELLATE CELLS ; INHIBITORS ; IDENTIFICATION ; RECOGNITION ; PROTEIN ; EXPRESSION ; REGULATOR ; RRMS
资助项目National Natural Science Foundation of China[81730100] ; National Natural Science Foundation of China[81874317] ; National Natural Science Foundation of China[82003783] ; National Natural Science Foundation of China[81722047] ; National Natural Science Foundation of China[21937005] ; National Natural Science Foundation of China[81670553] ; National Key R&D Program of China[2017YFA0506000] ; Fundamental Research Funds for the Central Universities[020814380161] ; China Postdoctoral Science Foundation[2020M671445]
WOS研究方向Biochemistry & Molecular Biology
语种英语
WOS记录号WOS:000768149100001
出版者OXFORD UNIV PRESS
源URL[http://119.78.100.183/handle/2S10ELR8/300021]  
专题新药研究国家重点实验室
通讯作者Xu, Qiang; Wu, Xingxin
作者单位1.Nanjing Univ, Chem & Biomed Innovat Ctr ChemB, Sch Life Sci, State Key Lab Pharmaceut Biotechnol, Nanjing 210023, Peoples R China
2.Nanjing Univ, Sch Life Sci, State Key Lab Pharmaceut Biotechnol, Nanjing 210023, Jiangsu, Peoples R China
3.Chinese Acad Sci, Drug Discovery & Design Ctr, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
4.Univ Chinese Acad Sci, 19 Yuquan Rd, Beijing 100049, Peoples R China
5.Jiangsu Simovay Pharmaceut Co Ltd, Dept Pharmacol, Nanjing 210042, Jiangsu, Peoples R China
6.Jiangsu Simovay Pharmaceut Co Ltd, Dept Pharmaceut Chem, Nanjing 210042, Jiangsu, Peoples R China
推荐引用方式
GB/T 7714		 Tan, Yang,Sun, Xueqing,Xu, Yizhu,et al. Small molecule targeting CELF1 RNA-binding activity to control HSC activation and liver fibrosis[J]. NUCLEIC ACIDS RESEARCH,2022:12.
APA Tan, Yang.,Sun, Xueqing.,Xu, Yizhu.,Tang, Bingjie.,Xu, Shuaiqi.,...&Wu, Xingxin.(2022).Small molecule targeting CELF1 RNA-binding activity to control HSC activation and liver fibrosis.NUCLEIC ACIDS RESEARCH,12.
MLA Tan, Yang,et al."Small molecule targeting CELF1 RNA-binding activity to control HSC activation and liver fibrosis".NUCLEIC ACIDS RESEARCH (2022):12.

入库方式： OAI收割

来源：上海药物研究所

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