Design, Synthesis, and Biological Evaluation of Peptidomimetic Tetrahydropyrrole Spirodihydroindolones as SARS-CoV-2 3CL Protease Inhibitors
The 3CL protease (3CL<sup>pro</sup>) 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, <b>13c</b> and <b>17d</b> exhibited obvious 3CL<sup>pro</sup> inhibitory activities with IC<sub>50</sub> = 3.71 and 6.21 nM, respectively. In metabolic stability testing of liver microsomes, compound <b>13c</b> showed improved stability in human liver microsomes. In addition, <b>13c</b> displayed significant anti-SARS-CoV-2 activity and high safety in Vero E6 cells (EC<sub>50</sub> = 19.26 nM, SI > 400). Further investigations indicated that <b>13c</b> showed potent activity against HCoV-OC43 and favorable safety in Huh7 cells (EC<sub>50</sub> = 61 nM, SI > 100). These findings suggest that compound <b>13c</b> is a promising lead compound in the development of novel 3CL<sup>pro</sup> inhibitors.
Authors
- Jingshan Shen (ORCID: https://orcid.org/0000-0001-9679-9934)
- Tianwen Hu (ORCID: https://orcid.org/0000-0003-2997-8232)
- Weiliang Zhu (ORCID: https://orcid.org/0000-0001-6699-5299)
- Qiumeng Zhang (ORCID: https://orcid.org/0000-0003-4404-4841)
- Leike Zhang (ORCID: https://orcid.org/0000-0002-2593-2571)
- Zhihe Zhao (ORCID: https://orcid.org/0000-0003-2955-1706)
- Lei Hu (ORCID: https://orcid.org/0009-0005-5543-3019)
- Xiangrui Jiang (ORCID: https://orcid.org/0000-0001-5941-6105)
- Zhijian Xu (ORCID: https://orcid.org/0000-0002-3063-8473)
- Yan Zhang (ORCID: https://orcid.org/0000-0002-2033-7538)
- Lei Yang (ORCID: https://orcid.org/0000-0002-9039-8520)
- Shujing Zhang
- Wenjie Cui (ORCID: https://orcid.org/0009-0003-5360-7324)
- Yumin Zhang (ORCID: https://orcid.org/0000-0003-2806-8448)
- Jin Suo
- Haiguo Sun
Institutions
- Delta Air Lines (United States) (US)
- Chinese Academy of Sciences (CN)
- Anhui University of Traditional Chinese Medicine (CN)
- Wuhan Institute of Virology (CN)
- Shanghai Institute of Materia Medica (CN)
- Advanced Research Institute (US)
- University of Chinese Academy of Sciences (CN)
- State Key Laboratory of Drug Research
- Huazhong University of Science and Technology (CN)
Publication Details
- Journal
- ACS Medicinal Chemistry Letters
- Published
- 2025-04-14
- DOI
- https://doi.org/10.1021/acsmedchemlett.4c00637
- Primary Topic
- Computational Drug Discovery Methods
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences