Development of Orally Bioavailable Octahydroindole-Based Peptidomimetic Derivative as a Broad-Spectrum Inhibitor against HCoV-OC43 and SARS-CoV-2

作者：Shulei Hu, Yumin Zhang, Chenchen Wang, Jian Li, Haixia Su, Xiong Xie, Jiang Wang, Jinlin Wang, Junyuan Cao, Xiaofei He, Yechun Xu, Leike Zhang, Wenhao Dai, Hong Liu · 发表于：Journal of Medicinal Chemistry · 年份：2025 · DOI：10.1021/acs.jmedchem.4c03024 · 被引用次数：8 · 研究领域：Computational Drug Discovery Methods、Influenza Virus Research Studies、SARS-CoV-2 and COVID-19 Research

A series of novel M pro 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 28f showed strong inhibitory activity against M pro s and exhibited broad-spectrum anticoronavirus activity with EC 50 values ranging from 0.027 to 4.41 μM. Besides, this compound displayed potent antiviral activity against EV71. Compared to FB2001, 28f 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 28f could significantly reduce the viral loads of HCoV-OC43 in mice, and compound 28f could also effectively reduce lung viral loads in a K18-hACE2 transgenic mouse model without ritonavir. Taken together, compound 28f is a promising orally bioavailable broad-spectrum antiviral drug candidate that deserves further research.