Thiazole-fused thiazoliniums with ketone warheads as covalent inhibitors targeting Cys44 of SARS-CoV-2 3CLpro
文献类型：期刊论文
| 作者 | Cao, Qizhen3,5; Zhang, Zhaoqin4; Zhu, Guanghao4; Dong, Sanfeng3; Sun, Xue4; Song, Yuqing4; Zhang, Ya4; Cai, Tingting3; Zhang, Xinben3; Zhang, Yong3 |
| 刊名 | CHEMICO-BIOLOGICAL INTERACTIONS
 |
| 出版日期 | 2025-09-05 |
| 卷号 | 418页码:12 |
| 关键词 | Thiazole-fused thiazolinium Ketone Covalent inhibitor SARS-CoV-2 3CLpro Cys44 |
| ISSN号 | 0009-2797 |
| DOI | 10.1016/j.cbi.2025.111620 |
| 英文摘要 | The 3-chymotrypsin-like protease (3CLpro) is a crucial enzyme for the replication of coronaviruses, notable for its high conservation across viral species and the lack of human analogs. These characteristics make it a prime target for the development of broad-spectrum antiviral medications. In this work, we incorporated the zolinium as a hydrophilic group and a ketone as the covalent warhead to develop novel agents targeting SARS-CoV-2 3CLpro. We designed and synthesized 60 derivatives to systematically study their structure-activity relationships (SAR). Of these, compound 46 demonstrated the most potent inhibition against 3CLpro (IC50 = 1.75 +/- 0.039 mu M) and good selectivity against other five enzymes, with reasonable chemical stability and rapid reactivity with cysteine. Mass spectrometry-based peptide mapping revealed that the ketone group of compound 46 covalently modified Cys44 of SARS-CoV-2 3CLpro. The inactivation kinetics indicated that compound 46 reduced the 3CLpro activity in a time- and dose-dependent manner, with an inactivation efficiency constant (kinact/Ki) of 0.011 min-1 mu M-1. Further covalent docking and molecular dynamics simulations elucidated the binding mechanism involving the disruption of protein's dimer interface and stability, which was partially validated by Native-PAGE analysis. Moreover, compound 46 exhibited negligible cytotoxicity and good metabolic stability in liver microsome assays, positioning it as a promising covalent lead for the advancement of broad-spectrum anti-coronavirus therapies. |
| WOS关键词 | DISCOVERY ; PHARMACOKINETICS ; IDENTIFICATION ; PROTEINASE ; METABOLISM ; BINDING |
| 资助项目 | NSFC[22277129] ; NSFC[82273897] ; National Key Research and Development Program of China[2022YFA1004304] ; Science for Life Laboratory |
| WOS研究方向 | Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Toxicology |
| 语种 | 英语 |
| WOS记录号 | WOS:001525414300001 |
| 出版者 | ELSEVIER IRELAND LTD |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/318834]  |
| 专题 | 国家级研究中心_原创新药研究全国重点实验室 |
| 通讯作者 | Zhu, Weiliang; Ge, Guangbo; Li, Bo |
| 作者单位 | 1.Uppsala Univ, Dept Chem BMC, Sci Life Lab, S-75123 Uppsala, Sweden 2.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China 3.Chinese Acad Sci, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China 4.Shanghai Univ Tradit Chinese Med, Inst Interdisciplinary Integrat Med Res, Shanghai Frontiers Sci Ctr TCM Chem Biol, Shanghai 201203, Peoples R China 5.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210046, Peoples R China |
| 推荐引用方式 GB/T 7714 | Cao, Qizhen,Zhang, Zhaoqin,Zhu, Guanghao,et al. Thiazole-fused thiazoliniums with ketone warheads as covalent inhibitors targeting Cys44 of SARS-CoV-2 3CLpro[J]. CHEMICO-BIOLOGICAL INTERACTIONS,2025,418:12. |
| APA | Cao, Qizhen.,Zhang, Zhaoqin.,Zhu, Guanghao.,Dong, Sanfeng.,Sun, Xue.,...&Li, Bo.(2025).Thiazole-fused thiazoliniums with ketone warheads as covalent inhibitors targeting Cys44 of SARS-CoV-2 3CLpro.CHEMICO-BIOLOGICAL INTERACTIONS,418,12. |
| MLA | Cao, Qizhen,et al."Thiazole-fused thiazoliniums with ketone warheads as covalent inhibitors targeting Cys44 of SARS-CoV-2 3CLpro".CHEMICO-BIOLOGICAL INTERACTIONS 418(2025):12. |
入库方式： OAI收割
来源：上海药物研究所
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