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, and Joseph Cherian
J. Med. Chem. 2025
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.
