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Discovery of Novel Nonpeptidic and Noncovalent Small Molecule 3CLpro Inhibitors as anti-SARS-CoV-2 Drug Candidate

文献类型：期刊论文

作者Jiang, Zhidong10,11,12,13; Feng, Bo9,10,11; Chen, Lu5,6; Nie, Tianqing7,8,12; Chen, Shizhao4; Wang, Li10,11; Liu, Hui3,10,11; Yu, Ting10,11; Zhang, Yumin5; Zheng, Miao9,10,11
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2024-07-29
卷号67期号:15页码:12760-12783
ISSN号0022-2623
DOI10.1021/acs.jmedchem.4c00739
通讯作者Zang, Yi(yzang@lglab.ac.cn) ; Su, Haixia(suhaixia1@simm.ac.cn) ; Zhang, Leike(zhangleike@wh.iov.cn) ; Li, Jia(jli@simm.ac.cn) ; Zhou, Yu(zhouyu@simm.ac.cn)
英文摘要SARS-CoV-2 has still been threatening global public health with its emerging variants. Our previous work reported lead compound JZD-07 that displayed good 3CL(pro) inhibitory activity. Here, an in-depth structural optimization for JZD-07 was launched to obtain more desirable drug candidates for the therapy of SARS-CoV-2 infection, in which 54 novel derivatives were designed and synthesized by a structure-based drug design strategy. Among them, 24 compounds show significantly enhanced 3CL(pro) inhibitory potencies with IC50 values less than 100 nM, and 11 compounds dose-dependently inhibit the replication of the SARS-CoV-2 delta variant. In particular, compound 49 has the most desirable antiviral activity with EC50 of 0.272 +/- 0.013 mu M against the delta variant, which was more than 20 times stronger than JZD-07. Oral administration of 49 could significantly reduce the lung viral copies of mice, exhibiting a more favorable therapeutic potential. Overall, this investigation presents a promising drug candidate for further development to treat SARS-CoV-2 infection.
WOS关键词COVALENT INHIBITORS
资助项目National Natural Science Foundation of China[82151219] ; National Natural Science Foundation of China[82130105] ; Strategic Priority Research Program of the Chinese Academy of Sciences[SIMM010109] ; Strategic Priority Research Program of the Chinese Academy of Sciences[SIMM010111] ; Shanghai Institute of Materia Medica[SIMM0120231003] ; Qiusuo Outstanding Youth Project of Lingang Laboratory[LG-QS-202205-02] ; Taishan Scholars Program[tstp0648]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001280437200001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/312541]  
专题新药研究国家重点实验室
通讯作者Zang, Yi; Su, Haixia; Zhang, Leike; Li, Jia; Zhou, Yu
作者单位1.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Shandong, Peoples R China
2.Hubei Jiangxia Lab, Wuhan 430200, Peoples R China
3.Henan Univ, Pharmaceut Coll, Kaifeng 475004, Peoples R China
4.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
5.Chinese Acad Sci, State Key Lab Virol, Wuhan Inst Virol, Ctr Biosafety Megasci, Wuhan 430071, Peoples R China
6.China Three Gorges Univ, Coll Biol & Pharmaceut Sci, Yichang 443002, Hubei, Peoples R China
7.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
8.ShanghaiTech Univ, Sch Phys Sci & Technol, Shanghai 201210, Peoples R China
9.Shenyang Pharmaceut Univ, Shenyang 110016, Peoples R China
10.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
推荐引用方式
GB/T 7714		 Jiang, Zhidong,Feng, Bo,Chen, Lu,et al. Discovery of Novel Nonpeptidic and Noncovalent Small Molecule 3CLpro Inhibitors as anti-SARS-CoV-2 Drug Candidate[J]. JOURNAL OF MEDICINAL CHEMISTRY,2024,67(15):12760-12783.
APA Jiang, Zhidong.,Feng, Bo.,Chen, Lu.,Nie, Tianqing.,Chen, Shizhao.,...&Zhou, Yu.(2024).Discovery of Novel Nonpeptidic and Noncovalent Small Molecule 3CLpro Inhibitors as anti-SARS-CoV-2 Drug Candidate.JOURNAL OF MEDICINAL CHEMISTRY,67(15),12760-12783.
MLA Jiang, Zhidong,et al."Discovery of Novel Nonpeptidic and Noncovalent Small Molecule 3CLpro Inhibitors as anti-SARS-CoV-2 Drug Candidate".JOURNAL OF MEDICINAL CHEMISTRY 67.15(2024):12760-12783.

入库方式： OAI收割

来源：上海药物研究所

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