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Publications

Journal Article Epublish

PubMed: 40365415 DOI: 10.1021/acsmedchemlett.4c00637

Design, Synthesis, and Biological Evaluation of Peptidomimetic Tetrahydropyrrole Spirodihydroindolones as SARS-CoV-2 3CL Protease Inhibitors.

ACS Med Chem Lett 16(5):790-796

Authors: Liuyan Hu, Zhi Zhao, Shujing Zhang, Lei Yang, Wenjie Cui, Tianwen Hu, Jin Suo, Haiguo Sun, Qiumeng Zhang, Leike Zhang, Weiliang Zhu, Zhijian Xu, Yumin Zhang, Xiangrui Jiang, Yan Zhang, Jingshan Shen

Affiliations

  • School of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, China. Yangtze Delta Drug Advanced Research Institute and Yangtze Delta Pharmaceutical College, Nantong 226133, China.
  • Yangtze Delta Drug Advanced Research Institute and Yangtze Delta Pharmaceutical College, Nantong 226133, China.
  • Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China.
  • State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
  • Vigonvita Shanghai Co. Ltd, Shanghai 201210, China.
  • State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
  • State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei 430071, China.
  • Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, China.
  • State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China. Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, China.

Abstract

The 3CL protease (3CL pro) of SARS-CoV-2 is a key enzyme that plays an essential role in mediating viral replication and transcription. In this study, we synthesized and evaluated a series of peptidomimetic compounds containing a tetrahydropyrrole spirodihydroindolone moiety. Among the target compounds, 13c and 17d exhibited obvious 3CL pro inhibitory activities with IC 50 = 3.71 and 6.21 nM, respectively. In metabolic stability testing of liver microsomes, compound 13c showed improved stability in human liver microsomes. In addition, 13c displayed significant anti-SARS-CoV-2 activity and high safety in Vero E6 cells (EC 50 = 19.26 nM, SI > 400). Further investigations indicated that 13c showed potent activity against HCoV-OC43 and favorable safety in Huh7 cells (EC 50 = 61 nM, SI > 100). These findings suggest that compound 13c is a promising lead compound in the development of novel 3CL pro inhibitors.

MeSH

Cells, Sars-Cov-2, Safety, Microsomes, Liver, Liver, Peptidomimetics, Peptide Hydrolases, Protease Inhibitors, Severe Acute Respiratory Syndrome-Related Coronavirus, Microsomes