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J Med Chem
. 2025 Aug 7.
doi: 10.1021/acs.jmedchem.5c00581. Online ahead of print. Discovery of an Orally Bioavailable Reversible Covalent SARS-CoV-2 Mpro Inhibitor with Pan-Coronavirus Activity
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
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.
. 2025 Aug 7.
doi: 10.1021/acs.jmedchem.5c00581. Online ahead of print. Discovery of an Orally Bioavailable Reversible Covalent SARS-CoV-2 Mpro Inhibitor with Pan-Coronavirus Activity
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
- PMID: 40773370
- DOI: 10.1021/acs.jmedchem.5c00581
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.