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

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

  • J Med Chem. 2025 Jun 12;68(11):10823-10844. doi: 10.1021/acs.jmedchem.4c03024.
Shulei Hu 1 2,  Yumin Zhang 3,  Chenchen Wang 2 4 5,  Jian Li 2,  Haixia Su 2,  Xiong Xie 2,  Jiang Wang 2 6,  Jinlin Wang 2 5,  Junyuan Cao 3 7,  Xiaofei He 1 2,  Yechun Xu 2 4 5,  Leike Zhang 3 7,  Wenhao Dai 2 4 5,  Hong Liu 1 2 4 5
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, China Pharmaceutical University, 639 Longmian Avenue, Jiangning District, Nanjing 211198, China.
  • 2 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
  • 3 State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan 430071, Hubei, China.
  • 4 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
  • 5 University of Chinese Academy of Sciences, Beijing 100049, China.
  • 6 Lingang Laboratory, Shanghai 200031, China.
  • 7 Hubei Jiangxia Laboratory, Wuhan 430200, China.
PMID: 40400488 DOI: 10.1021/acs.jmedchem.4c03024
Abstract

A series of novel Mpro 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 Mpros and exhibited broad-spectrum anticoronavirus activity with EC50 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.

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