Development of Orally Bioavailable Octahydroindole-Based Peptidomimetic Derivative as a Broad-Spectrum Inhibitor against HCoV-OC43 and SARS-CoV-2
A series of novel M<sup>pro</sup> inhibitors was designed and synthesized to combat the coronavirus, such as HCoV-OC43 and SARS-CoV-2, and several compounds showed comparable antiviral activity to nirmatrelvir. Among them, an octahydroindole-based peptidomimetic covalent inhibitor <b>28f</b> showed strong inhibitory activity against M<sup>pro</sup>s and exhibited broad-spectrum anticoronavirus activity with EC<sub>50</sub> values ranging from 0.027 to 4.41 μM. Besides, this compound displayed potent antiviral activity against EV71. Compared to <b>FB2001</b>, <b>28f</b> displayed better pharmacokinetic properties, and the value of oral bioavailability in CD-1 mice and Beagle dogs was improved to 10.4 and 10.2%, respectively. In addition, oral treatment with <b>28f</b> could significantly reduce the viral loads of HCoV-OC43 in mice, and compound <b>28f</b> could also effectively reduce lung viral loads in a K18-hACE2 transgenic mouse model without ritonavir. Taken together, compound <b>28f</b> is a promising orally bioavailable broad-spectrum antiviral drug candidate that deserves further research.
Authors
- Yechun Xu (ORCID: https://orcid.org/0000-0002-1581-6155)
- Xiong Xie
- Xiaofei He (ORCID: https://orcid.org/0000-0003-2983-0289)
- Wenhao Dai (ORCID: https://orcid.org/0000-0001-8508-7130)
- Shulei Hu
- Jinlin Wang (ORCID: https://orcid.org/0000-0003-4625-7605)
- Leike Zhang (ORCID: https://orcid.org/0000-0002-2593-2571)
- Jiang Wang (ORCID: https://orcid.org/0000-0003-1705-4905)
- Chenchen Wang (ORCID: https://orcid.org/0000-0003-1910-5518)
- Jian Li (ORCID: https://orcid.org/0000-0001-9434-7803)
- Hong Shu Liu (ORCID: https://orcid.org/0000-0003-3685-6268)
- Haixia Su
- Junyuan Cao (ORCID: https://orcid.org/0009-0004-0758-0092)
- Yumin Zhang (ORCID: https://orcid.org/0000-0003-2806-8448)
Institutions
- China Pharmaceutical University (CN)
- Chinese Academy of Sciences (CN)
- Wuhan Institute of Virology (CN)
- Shanghai Institute of Materia Medica (CN)
- Institute for Advanced Study (DE)
- University of Chinese Academy of Sciences (CN)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-05-22
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c03024
- Citations
- 5
- Primary Topic
- Computational Drug Discovery Methods
- Type
- article
- Field-Weighted Citation Impact
- 7.52
Funders
- National Natural Science Foundation of China
- Chinese Academy of Sciences
- Natural Science Foundation of Hubei Province
- National Key Research and Development Program of China