Discovery and Mechanism Study of SARS-CoV-2 3C-like Protease Inhibitors with a New Reactive Group

doi:10.1021/acs.jmedchem.3c00818

	Discovery and Mechanism Study of SARS-CoV-2 3C-like Protease Inhibitors with a New Reactive Group
	Ren, Pengxuan1,2 ; Li, Hui 3,4; Nie, Tianqing 4; Jian, Xiaoqin 5; Yu, Changyue 4; Li, Jian 4; Su, Haixia 4; Zhang, Xianglei1,2 ; Li, Shiwei1,2 ; Yang, Xin1,2 ; Peng, Chao 6; Yin, Yue 6; Zhang, Leike 5; Xu, Yechun 4,7; Liu, Hong 3,4,7; Bai, Fang1,2,8,9
	2023-08-01
发表期刊	JOURNAL OF MEDICINAL CHEMISTRY (IF:6.8[JCR-2023],7.1[5-Year])
ISSN	0022-2623
EISSN	1520-4804
发表状态	已发表
DOI	10.1021/acs.jmedchem.3c00818
摘要	3CL(pro) is an attractive target for the treatmentofCOVID-19. Using the scaffold hopping strategy, we identified a potentinhibitor of 3CL(pro) (3a) that contains a thiocyanatemoiety as a novel warhead that can form a covalent bond with Cys145of the protein. Tandem mass spectrometry (MS/MS) and X-ray crystallographyconfirmed the mechanism of covalent formation between 3a and the protein in its catalytic pocket. Moreover, several analoguesof compound 3a were designed and synthesized. Among them,compound 3h shows the best inhibition of 3CL(pro) with an IC50 of 0.322 & mu;M and a k (inact)/K (i) value of 1669.34M(-1) s(-1), and it exhibits goodtarget selectivity for 3CL(pro) against host proteases. Compound 3c inhibits SARS-CoV-2 in Vero E6 cells (EC50 =2.499 & mu;M) with low cytotoxicity (CC50 > 200 & mu;M).These studies provide ideas and insights to explore and develop new3CL(pro) inhibitors in the future.
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收录类别	SCI
语种	英语
资助项目	Science and Technology Commission of Shanghai Municipality grants[
WOS研究方向	Pharmacology & Pharmacy
WOS类目	Chemistry, Medicinal
WOS记录号	WOS:001051340300001
出版者	AMER CHEMICAL SOC
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/325788
专题	生命科学与技术学院信息科学与技术学院免疫化学研究所生命科学与技术学院_硕士生生命科学与技术学院_博士生生命科学与技术学院_本科生免疫化学研究所_PI研究组_白芳组
共同第一作者	Li, Hui; Nie, Tianqing; Jian, Xiaoqin
通讯作者	Zhang, Leike; Xu, Yechun; Liu, Hong; Bai, Fang
作者单位	1.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China 2.ShanghaiTech Univ, Shanghai Inst Adv Immunochem Studies, Shanghai 201210, Peoples R China 3.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China 4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 5.Chinese Acad Sci, Wuhan Inst Virol, Ctr Biosafety Mega Sci, State Key Lab Virol, Wuhan 430071, Peoples R China 6.Chinese Acad Sci, Shanghai Adv Res Inst, Natl Facil Prot Sci Shanghai, Shanghai 201210, Peoples R China 7.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China 8.ShanghaiTech Univ, Sch Informat Sci & Technol, Shanghai 201210, Peoples R China 9.Shanghai Clin Res & Trial Ctr, Shanghai 201210, Peoples R China
第一作者单位	生命科学与技术学院; 免疫化学研究所
通讯作者单位	生命科学与技术学院; 免疫化学研究所; 信息科学与技术学院
第一作者的第一单位	生命科学与技术学院
推荐引用方式 GB/T 7714	Ren, Pengxuan,Li, Hui,Nie, Tianqing,et al. Discovery and Mechanism Study of SARS-CoV-2 3C-like Protease Inhibitors with a New Reactive Group[J]. JOURNAL OF MEDICINAL CHEMISTRY,2023.
APA	Ren, Pengxuan.,Li, Hui.,Nie, Tianqing.,Jian, Xiaoqin.,Yu, Changyue.,...&Bai, Fang.(2023).Discovery and Mechanism Study of SARS-CoV-2 3C-like Protease Inhibitors with a New Reactive Group.JOURNAL OF MEDICINAL CHEMISTRY.
MLA	Ren, Pengxuan,et al."Discovery and Mechanism Study of SARS-CoV-2 3C-like Protease Inhibitors with a New Reactive Group".JOURNAL OF MEDICINAL CHEMISTRY (2023).