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

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资源类型：
Pubmed体系：
作者：
Huang Chong[1] ; Zeng Rui[1] ; Qiao Jingxin[1] ; Quan Baoxue[1] ; Luo Ronghua[2] ; Huang Qiao[3] ; Guo Nihong[3] ; Li Yueyue[1] ; Long Xinyan[2] ; Ma Ronggang[1] ; Xia Anjie[1] ; Fang Zhen[1] ; Wang Yifei[1] ; Li Yueshan[1] ; Zheng Yongtang[2] ; Li Linli[3] ; Lei Jian[1,4] ; Yang Shengyong[1] ;
机构： [1]Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China [2]Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Center for Biosafety Mega-Science, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, 650223, China [3]Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, 610041, China [4]National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
出处：
DOI： 10.1016/j.ejmech.2023.115657
ISSN：

关键词： SARS-CoV-2 Mpro inhibitor α-ketoamide derivatives Structure-activity relationship

摘要：
The SARS-CoV-2 main protease (Mpro, also named 3CLpro) 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 α-ketoamide derivatives as a new class of SARS-CoV-2 Mpro inhibitors. Structure-activity relationship (SAR) of these compounds was analyzed, which led to the identification of a potent Mpro inhibitor (27h) with an IC50 value of 10.9 nM. The crystal structure of Mpro in complex with 27h revealed that α-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 Mpro 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-CoV-2 Mpro and deserves further in-depth studies.Copyright © 2023 Elsevier Masson SAS. All rights reserved.

基金：
This research was supported by National Natural Science Foundation of China [82130104, 81930125, T2221004 (S.Y.), 82273787 (L.L.) and 22107081 (B.Q.)], National Key R&D Program of China [2022YFC2303700 (J L. & Y.T.Z) and 2021YFF0702004 (J.L.)], 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University [ZYGD18001, ZYXY21001 (S.Y.), and ZYYC21008 (J.L.)], the fast-track grants of SARS-CoV-2 research, West China Hospital, Sichuan University [HX-2019-nCoV-053 (S.Y.)], National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University [Z2021JC008 (J.L.)], the National Postdoctoral Program for Innovative Talents of China[BX2021204 (Y.L.)], the China Postdoctoral Science Foundation [2021M702374 (Y.L.)], Yunnan Key R & D Program [202103AC100005 (Y.T.Z)].
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2023]版：
大类 | 2 区 医学
小类 | 1 区 药物化学
最新[2023]版：
大类 | 2 区 医学
小类 | 1 区 药物化学
第一作者：
第一作者机构： [1]Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
共同第一作者：
通讯作者：
通讯机构： [1]Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China [4]National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
推荐引用方式(GB/T 7714)：
Huang Chong,Zeng Rui,Qiao Jingxin,et al.Discovery and structure-activity relationship studies of novel α-ketoamide derivatives targeting the SARS-CoV-2 main protease[J].European journal of medicinal chemistry.2023,259:115657.doi:10.1016/j.ejmech.2023.115657.
APA：
Huang Chong,Zeng Rui,Qiao Jingxin,Quan Baoxue,Luo Ronghua...&Yang Shengyong.(2023).Discovery and structure-activity relationship studies of novel α-ketoamide derivatives targeting the SARS-CoV-2 main protease.European journal of medicinal chemistry,259,
MLA：
Huang Chong,et al."Discovery and structure-activity relationship studies of novel α-ketoamide derivatives targeting the SARS-CoV-2 main protease".European journal of medicinal chemistry 259.(2023):115657

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