tetano
Editor, Senior Moderator
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 M[SUP]pro[/SUP] Inhibitor with Pan-Coronavirus Activity
Qian Wen Tan[SUP] 1 [/SUP], Subramanyam Vankadara[SUP] 1 [/SUP], Jia Yi Fong[SUP] 1 [/SUP], Yi Yang See[SUP] 1 [/SUP], Nithya Baburajendran[SUP] 1 [/SUP], Pearly Shuyi Ng[SUP] 1 [/SUP], Weijun Xu[SUP] 1 [/SUP], Yee Khoon Yeo[SUP] 1 [/SUP], Weiling Wang[SUP] 1 [/SUP], Choon Heng Low[SUP] 1 [/SUP], Li Hong Tan[SUP] 1 [/SUP], Eileen Gui Ju Tay[SUP] 1 [/SUP], Yun Xuan Wong[SUP] 1 [/SUP], Chuhui Huang[SUP] 1 [/SUP], Sandra Sim[SUP] 1 [/SUP], Shi Hua Ang[SUP] 1 [/SUP], Hannah Hui Min Toh[SUP] 1 [/SUP], Juliana Mohammad[SUP] 1 [/SUP], Gang Wang[SUP] 1 [/SUP], Boping Liu[SUP] 1 [/SUP], Shu Ting Tan[SUP] 1 [/SUP], Perlyn Zekui Kwek[SUP] 1 [/SUP], Monique Danielle Dawson[SUP] 1 [/SUP], Qin Yao Oh[SUP] 1 [/SUP], Xiaoying Koh[SUP] 1 [/SUP], Joma Joy[SUP] 1 [/SUP], May Ann Lee[SUP] 1 [/SUP], Walter Stunkel[SUP] 1 [/SUP], Vishal Pendharkar[SUP] 1 [/SUP], Hannes Hentze[SUP] 1 [/SUP], Siew Pheng Lim[SUP] 1 [/SUP], Kantharaj Ethirajulu[SUP] 1 [/SUP], C S Brian Chia[SUP] 1 [/SUP], Joseph Cherian[SUP] 1 [/SUP]
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 M[SUP]pro[/SUP], 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 M[SUP]pro[/SUP] Inhibitor with Pan-Coronavirus Activity
Qian Wen Tan[SUP] 1 [/SUP], Subramanyam Vankadara[SUP] 1 [/SUP], Jia Yi Fong[SUP] 1 [/SUP], Yi Yang See[SUP] 1 [/SUP], Nithya Baburajendran[SUP] 1 [/SUP], Pearly Shuyi Ng[SUP] 1 [/SUP], Weijun Xu[SUP] 1 [/SUP], Yee Khoon Yeo[SUP] 1 [/SUP], Weiling Wang[SUP] 1 [/SUP], Choon Heng Low[SUP] 1 [/SUP], Li Hong Tan[SUP] 1 [/SUP], Eileen Gui Ju Tay[SUP] 1 [/SUP], Yun Xuan Wong[SUP] 1 [/SUP], Chuhui Huang[SUP] 1 [/SUP], Sandra Sim[SUP] 1 [/SUP], Shi Hua Ang[SUP] 1 [/SUP], Hannah Hui Min Toh[SUP] 1 [/SUP], Juliana Mohammad[SUP] 1 [/SUP], Gang Wang[SUP] 1 [/SUP], Boping Liu[SUP] 1 [/SUP], Shu Ting Tan[SUP] 1 [/SUP], Perlyn Zekui Kwek[SUP] 1 [/SUP], Monique Danielle Dawson[SUP] 1 [/SUP], Qin Yao Oh[SUP] 1 [/SUP], Xiaoying Koh[SUP] 1 [/SUP], Joma Joy[SUP] 1 [/SUP], May Ann Lee[SUP] 1 [/SUP], Walter Stunkel[SUP] 1 [/SUP], Vishal Pendharkar[SUP] 1 [/SUP], Hannes Hentze[SUP] 1 [/SUP], Siew Pheng Lim[SUP] 1 [/SUP], Kantharaj Ethirajulu[SUP] 1 [/SUP], C S Brian Chia[SUP] 1 [/SUP], Joseph Cherian[SUP] 1 [/SUP]
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 M[SUP]pro[/SUP], 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.