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

  • J Med Chem. 2025 Aug 28;68(16):17087-17102. doi: 10.1021/acs.jmedchem.5c00581.
Qian Wen Tan  1 ,  Subramanyam Vankadara  1 ,  Jia Yi Fong  1 ,  Yi Yang See  1 ,  Nithya Baburajendran  1 ,  Pearly Shuyi Ng  1 ,  Weijun Xu  1 ,  Yee Khoon Yeo  1 ,  Weiling Wang  1 ,  Choon Heng Low  1 ,  Li Hong Tan  1 ,  Eileen Gui Ju Tay  1 ,  Yun Xuan Wong  1 ,  Chuhui Huang  1 ,  Sandra Sim  1 ,  Shi Hua Ang  1 ,  Hannah Hui Min Toh  1 ,  Juliana Mohammad  1 ,  Gang Wang  1 ,  Boping Liu  1 ,  Shu Ting Tan  1 ,  Perlyn Zekui Kwek  1 ,  Monique Danielle Dawson  1 ,  Qin Yao Oh  1 ,  Xiaoying Koh  1 ,  Joma Joy  1 ,  May Ann Lee  1 ,  Walter Stunkel  1 ,  Vishal Pendharkar  1 ,  Hannes Hentze  1 ,  Siew Pheng Lim  1 ,  Kantharaj Ethirajulu  1 ,  C S Brian Chia  1 ,  Joseph Cherian  1
Affiliations
  • 1. Experimental Drug Development Centre (EDDC), Agency for Science, Technology and Research (A*STAR), 10 Biopolis Road, Chromos #05-01, Singapore 138670, Republic of Singapore.
PMID: 40773370 DOI: 10.1021/acs.jmedchem.5c00581
Abstract

Resulting in several million deaths globally, the COVID-19 pandemic has highlighted the criticality of Antiviral drugs during a viral pandemic. Herein, we describe our efforts toward 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 mice, rats, dogs, and monkeys.

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