2. Academic Validation
  3. Discovery, synthesis and mechanism study of 2,3,5-substituted [1,2,4]-thiadiazoles as covalent inhibitors targeting 3C-Like protease of SARS-CoV-2

Discovery, synthesis and mechanism study of 2,3,5-substituted [1,2,4]-thiadiazoles as covalent inhibitors targeting 3C-Like protease of SARS-CoV-2

  • Eur J Med Chem. 2023 Jan 18;249:115129. doi: 10.1016/j.ejmech.2023.115129.
Pengxuan Ren 1,  Changyue Yu 2,  Ruxue Zhang 3,  Tianqing Nie 4,  Qiaoyu Hu 5,  Hui Li 4,  Xianglei Zhang 1,  Xueyuan Zhang 1,  Shiwei Li 1,  Lu Liu 1,  Wenhao Dai 2,  Jian Li 2,  Yechun Xu 6,  Haixia Su 7,  Leike Zhang 8,  Hong Liu 9,  Fang Bai 10
Affiliations

Affiliations

  • 1 School of Life Science and Technology, and Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China.
  • 2 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 3 State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, 430071, China.
  • 4 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
  • 5 School of Life Science and Technology, and Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China; East China Normal University, Innovation Center for AI and Drug Discovery, Shanghai, 200062, China.
  • 6 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China.
  • 7 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. Electronic address: suhaixia1@simm.ac.cn.
  • 8 State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, 430071, China. Electronic address: zhangleike@wh.iov.cn.
  • 9 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China. Electronic address: hliu@simm.ac.cn.
  • 10 School of Life Science and Technology, and Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China; School of Information Science and Technology, ShanghaiTech University, Shanghai, 201210, China; Shanghai Clinical Research and Trial Center, Shanghai, 201210, China. Electronic address: baifang@shanghaitech.edu.cn.
PMID: 36702052 DOI: 10.1016/j.ejmech.2023.115129
Abstract

The 3C-like protease (3CLpro) is essential for the replication and transcription of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), making it a promising target for the treatment of corona virus disease 2019 (COVID-19). In this study, a series of 2,3,5-substituted [1,2,4]-thiadiazole analogs were discovered to be able to inhibit 3CLpro as non-peptidomimetic covalent Binders at submicromolar levels, with IC50 values ranging from 0.118 to 0.582 μM. Interestingly, these compounds were also shown to inhibit PLpro with the same level of IC50 values, but had negligible effect on proteases such as chymotrypsin, Cathepsin B, and Cathepsin L. Subsequently, the Antiviral abilities of these compounds were evaluated in cell-based assays, and compound 6g showed potent Antiviral activity with an EC50 value of 7.249 μM. It was proposed that these compounds covalently bind to the catalytic cysteine 145 via a ring-opening metathesis reaction mechanism. To understand this covalent-binding reaction, we chose compound 6a, one of the identified hit compounds, as a representative to investigate the reaction mechanism in detail by combing several computational predictions and experimental validation. The process of ring-opening metathesis was theoretically studied using quantum chemistry calculations according to the transition state theory. Our study revealed that the 2,3,5-substituted [1,2,4]-thiadiazole group could covalently modify the catalytic cysteine in the binding pocket of 3CLpro as a potential warhead. Moreover, 6a was a known GPCR modulator, and our study is also a successful computational method-based drug-repurposing study.

Keywords

2,3,5-substituted [1,2,4]-thiadiazole; 3CL(pro); Covalent inhibitors; Ring-opening metathesis; SARS-CoV-2; Warhead.

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