Discovery of an Orally Bioavailable Reversible Covalent SARS-CoV-2 Mpro Inhibitor with Pan-Coronavirus Activity

Discovery of an Orally Bioavailable Reversible Covalent SARS-CoV-2 Mpro Inhibitor with Pan-Coronavirus Activity

Journal of Medicinal Chemistry

10.1021/acs.jmedchem.5c00581

https://doi.org/10.1021/acs.jmedchem.5c00581

Qian Wen Tan, Subramanyam Vankadara, Jia Yi Fong, Yi Yang See, Nithya Baburajendran, Pearly Shuyi Ng, Weijun Xu, Yee Khoon Yeo, Weiling Wang, Choon Heng Low, Li Hong Tan, Eileen Gui Ju Tay, Yun Xuan Wong, Chuhui Huang, Sandra Sim, Shi Hua Ang, Hannah Hui Min Toh, Juliana Mohammad, Gang Wang, Boping Liu, Shu Ting Tan, Perlyn Zekui Kwek, Monique Danielle Dawson, Qin Yao Oh, Xiaoying Koh, Joma Joy, May Ann Lee, Walter Stunkel, Vishal Pendharkar, Hannes Hentze, Siew Pheng Lim, Kantharaj Ethirajulu, C. S. Brian Chia, Joseph Cherian

coronavirus, SARS-CoV-2, protease, 3CLpro, Mpro, ketoamide, reversible inhibition

07 August 2025

Tan, Q. W., Vankadara, S., Fong, J. Y., See, Y. Y., Baburajendran, N., Ng, P. S., Xu, W., Yeo, Y. K., Wang, W., Low, C. H., Tan, L. H., Ju Tay, E. G., Wong, Y. X., Huang, C., Sim, S., Ang, S. H., Min Toh, H. H., Mohammad, J., Wang, G., … Cherian, J. (2025). Discovery of an Orally Bioavailable Reversible Covalent SARS-CoV-2 Mpro Inhibitor with Pan-Coronavirus Activity. Journal of Medicinal Chemistry, 68(16), 17087–17102. https://doi.org/10.1021/acs.jmedchem.5c00581

Resulting in several million deaths globally, the COVID-19 pandemic has spotlighted the criticality of antiviral drugs during a viral pandemic. Herein, we describe our efforts towards targeting SARS-CoV-2 Mpro, a key viral protease, which led to the discovery of compound 18, a reversible covalent inhibitor with potent antiviral activity against several clinical variants of SARS-CoV-2. Compound 18 demonstrated dose-dependent efficacy in a mouse-adapted SARS-CoV-2 infection model with favorable pharmacokinetic profiles in mouse, rat, dog, and monkey.

Publisher Copyright

This research / project is supported by the National Research Foundation (NRF) - Biomedical Science Open Collaborative Fund (BMS-OCF)
Grant Reference no. : 13/1/85/18/693

This research / project is supported by the National Research Foundation (NRF) - Industry Alignment Fund-Industry Collaboration Project (IAF-ICP)
Grant Reference no. : I1701E0009

This research is supported by core funding from: Experimental Drug Development Centre (EDDC)
Grant Reference no. : Human Health and Potential (HHP)

This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acs.jmedchem.5c00581.

https://oar.a-star.edu.sg/communities-collections/articles/22283

0022-2623
1520-4804

Experimental Drug Development Centre