Discovery and structure-activity relationship studies of novel a-ketoamide derivatives targeting the SARS-CoV-2 main protease

	Discovery and structure-activity relationship studies of novel a-ketoamide derivatives targeting the SARS-CoV-2 main protease
	Huang, C; Zeng, R; Qiao, JX; Quan, BX; Luo, RH; Huang, Q; Guo, NH; Li, YY; Long, XY; Ma, RG; Xia, AJ; Fang, Z; Wang, YF; Li, YS; Zheng, YT; Li, LL; Lei, J; Yang, SY
	2023
发表期刊	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
ISSN	0223-5234
卷号	259
摘要	The SARS-CoV-2 main protease (M-pro, also named 3CL(pro)) is a promising antiviral target against COVID-19 due to its functional importance in viral replication and transcription. Herein, we report the discovery of a series of a-ketoamide derivatives as a new class of SARS-CoV-2 M-pro inhibitors. Structure-activity relationship (SAR) of these compounds was analyzed, which led to the identification of a potent M-pro inhibitor (27h) with an IC50 value of 10.9 nM. The crystal structure of M-pro in complex with 27h revealed that a-ketoamide warhead covalently bound to Cys145s of the protease. In an in vitro antiviral assay, 27h showed excellent activity with an EC50 value of 43.6 nM, comparable to the positive control, Nirmatrelvir. This compound displayed high target specificity for M-pro against human proteases and low toxicity. It also possesses favorable pharmacokinetic properties. Overall, compound 27h could be a promising lead compound for drug discovery targeting SARS-CoV2 M-pro and deserves further in-depth studies.
收录类别	SCI
语种	英语
文献类型	期刊论文
条目标识符	http://ir.kiz.ac.cn/handle/152453/13970
专题	科研部门_分子免疫药理学（郑永唐）
推荐引用方式 GB/T 7714	Huang, C,Zeng, R,Qiao, JX,et al. Discovery and structure-activity relationship studies of novel a-ketoamide derivatives targeting the SARS-CoV-2 main protease[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2023,259.
APA	Huang, C.,Zeng, R.,Qiao, JX.,Quan, BX.,Luo, RH.,...&Yang, SY.(2023).Discovery and structure-activity relationship studies of novel a-ketoamide derivatives targeting the SARS-CoV-2 main protease.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,259.
MLA	Huang, C,et al."Discovery and structure-activity relationship studies of novel a-ketoamide derivatives targeting the SARS-CoV-2 main protease".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 259(2023).

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