中国科学院机构知识库网格
Chinese Academy of Sciences Institutional Repositories Grid
首页 机构 成果 学者
  
  1. CAS IR Grid
  2. 上海药物研究所
  3. 中国科学院上海药物研究所
Discovery of peptidomimetic spiropyrrolidine derivatives as novel 3CLpro inhibitors against SARS-CoV-2

文献类型：期刊论文

作者Guma, Samuel Desta2,6; Zhou, Zhaoyin4,5; Song, Kang4; Yang, Feipu2; Suo, Jin2; Zhang, Yan2; Bonku, Emmanuel Mintah2,6; Odilov, Abdullajon2,6; Tian, Guanghui1; Xu, Zhijian5,6
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2025-01-05
卷号281页码:22
关键词SARS-CoV-2 3CL pro inhibitors Peptidomimetics Spiropyrrolidine derivatives
ISSN号0223-5234
DOI10.1016/j.ejmech.2024.117004
通讯作者Zhang, Qiumeng(qmzhang@simm.ac.cn) ; Zhu, Weiliang(wlzhu@simm.ac.cn) ; Shen, Jingshan(shenjingshan@simm.ac.cn)
英文摘要Given the high pathogenicity and rapid mutation rates of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), it is imperative to sustain efforts in drug research and development. Herein, we present the design, synthesis, and evaluation of peptidomimetic spiropyrrolidine derivatives as potent 3CLpro inhibitors against SARS-CoV-2. Among the synthesized derivatives, several compounds exhibited high potency in inhibiting 3CLpro, with IC50 values ranging from 21 nM to 53 nM. Notably, compounds 9b and 9h displayed improved enzymatic inhibition (IC50 = 25 nM and 21 nM, respectively) compared to nirmatrelvir (47 nM). Compound 9b showed enhanced stability in human and mouse liver microsomes compared to nirmatrelvir, whereas 9h exhibited similar stability to nirmatrelvir in both species. Furthermore, compound 9h displayed exceptional potency in cellular assays targeting the SARS-CoV-2 replicon within Huh7 cells, with a single-digit nanomolar activity that is 5.6 times better than that of nirmatrelvir. In a pharmacokinetic study in mice (PO, 20 mg/kg), compound 9h exhibited a prolonged plasma half-life (T 1/2 = 2.58 h) compared to nirmatrelvir (T 1/2 = 0.51 h) and demonstrated an AUC (0-t) value (1106 h*ng/mL) equivalent to that of nirmatrelvir (1023 h*ng/mL). These findings indicate that compound 9h is a promising lead for developing a novel 3CLpro inhibitor against SARSCoV-2.
WOS关键词PROTEASE ; DESIGN ; POTENT
资助项目Shanghai Institute of Materia Medica, Chinese Academy of Sciences[SIMM0120231003] ; Shanghai Institute of Materia Medica, Chinese Academy of Sciences[CASIMM0120234003] ; National Natural Science Foundation of China[U22A20379] ; Alliance of International Science Organizations (ANSO) through the ANSO Scholarship for Young Talents
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001353967100001
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
源URL[http://119.78.100.183/handle/2S10ELR8/314403]  
专题中国科学院上海药物研究所
通讯作者Zhang, Qiumeng; Zhu, Weiliang; Shen, Jingshan
作者单位1.Vigonvita Life Sci Co Ltd, 108 Yuxin Rd, Suzhou Ind Pk, Suzhou 215123, Jiangsu, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, 501 Haike Rd, Shanghai 201203, Peoples R China
3.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Shandong, Peoples R China
4.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
6.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China
推荐引用方式
GB/T 7714		 Guma, Samuel Desta,Zhou, Zhaoyin,Song, Kang,et al. Discovery of peptidomimetic spiropyrrolidine derivatives as novel 3CLpro inhibitors against SARS-CoV-2[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2025,281:22.
APA Guma, Samuel Desta.,Zhou, Zhaoyin.,Song, Kang.,Yang, Feipu.,Suo, Jin.,...&Shen, Jingshan.(2025).Discovery of peptidomimetic spiropyrrolidine derivatives as novel 3CLpro inhibitors against SARS-CoV-2.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,281,22.
MLA Guma, Samuel Desta,et al."Discovery of peptidomimetic spiropyrrolidine derivatives as novel 3CLpro inhibitors against SARS-CoV-2".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 281(2025):22.

入库方式： OAI收割

来源：上海药物研究所

浏览0
下载0
收藏0
其他版本

除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。