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

  • ACS Med Chem Lett. 2025 Apr 14;16(5):790-796. doi: 10.1021/acsmedchemlett.4c00637.
Liuyan Hu  1  2 ,  Zhi Zhao  2 ,  Shujing Zhang  3 ,  Lei Yang  4  5 ,  Wenjie Cui  6 ,  Tianwen Hu  6 ,  Jin Suo  4 ,  Haiguo Sun  4  5 ,  Qiumeng Zhang  4 ,  Leike Zhang  7 ,  Weiliang Zhu  4  5 ,  Zhijian Xu  4  5 ,  Yumin Zhang  7 ,  Xiangrui Jiang  8  4  5 ,  Yan Zhang  4  5  8 ,  Jingshan Shen  4  5
Affiliations
  • 1. School of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, China.
  • 2. Yangtze Delta Drug Advanced Research Institute and Yangtze Delta Pharmaceutical College, Nantong 226133, China.
  • 3. Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China.
  • 4. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 5. University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
  • 6. Vigonvita Shanghai Co., Ltd, Shanghai 201210, China.
  • 7. State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei 430071, China.
  • 8. Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, China.
PMID: 40365415 DOI: 10.1021/acsmedchemlett.4c00637
Abstract

The 3CL protease (3CLpro) 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 3CLpro inhibitory activities with IC50 = 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 (EC50 = 19.26 nM, SI > 400). Further investigations indicated that 13c showed potent activity against HCoV-OC43 and favorable safety in Huh7 cells (EC50 = 61 nM, SI > 100). These findings suggest that compound 13c is a promising lead compound in the development of novel 3CLpro inhibitors.

Products