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Development of Orally Bioavailable Octahydroindole-Based Peptidomimetic Derivative as a Broad-Spectrum Inhibitor against HCoV-OC43 and SARS-CoV-2

文献类型：期刊论文

作者Hu, Shulei6,7; Zhang, Yumin5; Wang, Chenchen2,3,6; Li, Jian6; Su, Haixia6; Xie, Xiong6; Wang, Jiang1,6; Wang, Jinlin2,6; Cao, Junyuan4,5; He, Xiaofei6,7
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2025-05-22
卷号68期号:11页码:10823-10844
ISSN号0022-2623
DOI10.1021/acs.jmedchem.4c03024
英文摘要A series of novel Mpro inhibitors was designed and synthesized to combat the coronavirus, such as HCoV-OC43 and SARS-CoV-2, and several compounds showed comparable antiviral activity to nirmatrelvir. Among them, an octahydroindole-based peptidomimetic covalent inhibitor 28f showed strong inhibitory activity against Mpros and exhibited broad-spectrum anticoronavirus activity with EC50 values ranging from 0.027 to 4.41 mu M. Besides, this compound displayed potent antiviral activity against EV71. Compared to FB2001, 28f displayed better pharmacokinetic properties, and the value of oral bioavailability in CD-1 mice and Beagle dogs was improved to 10.4 and 10.2%, respectively. In addition, oral treatment with 28f could significantly reduce the viral loads of HCoV-OC43 in mice, and compound 28f could also effectively reduce lung viral loads in a K18-hACE2 transgenic mouse model without ritonavir. Taken together, compound 28f is a promising orally bioavailable broad-spectrum antiviral drug candidate that deserves further research.
WOS关键词COVALENT INHIBITORS ; PROTEASE INHIBITOR ; HUMAN CORONAVIRUS ; DISCOVERY ; DISEASE ; DESIGN
资助项目National Natural Science Foundation of China[82130105] ; National Natural Science Foundation of China[22107107] ; National Natural Science Foundation of China[82173654] ; National Natural Science Foundation of China[82341091] ; National Natural Science Foundation of China[82311530775] ; National Natural Science Foundation of China[U22A20379] ; National Natural Science Foundation of China[2023292] ; Youth Innovation Promotion Association CAS[2021YFC2300700] ; National Key Research and Development Plan of China[2022CFA099] ; Hubei Natural Science Foundation for Distinguished Young Scholars
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001493302700001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/317935]  
专题新药研究国家重点实验室
通讯作者Xu, Yechun; Zhang, Leike; Dai, Wenhao; Liu, Hong
作者单位1.Lingang Lab, Shanghai 200031, Peoples R China
2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
3.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
4.Hubei Jiangxia Lab, Wuhan 430200, Peoples R China
5.Chinese Acad Sci, Ctr Biosafety Mega Sci, Wuhan Inst Virol, State Key Lab Virol, Wuhan 430071, Hubei, Peoples R China
6.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
7.China Pharmaceut Univ, Dept Med Chem, Nanjing 211198, Peoples R China
推荐引用方式
GB/T 7714		 Hu, Shulei,Zhang, Yumin,Wang, Chenchen,et al. Development of Orally Bioavailable Octahydroindole-Based Peptidomimetic Derivative as a Broad-Spectrum Inhibitor against HCoV-OC43 and SARS-CoV-2[J]. JOURNAL OF MEDICINAL CHEMISTRY,2025,68(11):10823-10844.
APA Hu, Shulei.,Zhang, Yumin.,Wang, Chenchen.,Li, Jian.,Su, Haixia.,...&Liu, Hong.(2025).Development of Orally Bioavailable Octahydroindole-Based Peptidomimetic Derivative as a Broad-Spectrum Inhibitor against HCoV-OC43 and SARS-CoV-2.JOURNAL OF MEDICINAL CHEMISTRY,68(11),10823-10844.
MLA Hu, Shulei,et al."Development of Orally Bioavailable Octahydroindole-Based Peptidomimetic Derivative as a Broad-Spectrum Inhibitor against HCoV-OC43 and SARS-CoV-2".JOURNAL OF MEDICINAL CHEMISTRY 68.11(2025):10823-10844.

入库方式： OAI收割

来源：上海药物研究所

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