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. 2025 Apr 14;16(5):790-796.
doi: 10.1021/acsmedchemlett.4c00637. eCollection 2025 May 8.

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

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

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

Liuyan Hu et al. ACS Med Chem Lett. .

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.

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Conflict of interest statement

The authors declare no competing financial interest.

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