9KGR

Discovery of an orally bioavailable reversible covalent SARS-CoV-2 Mpro inhibitor with pan-coronavirus activity

This is a non-PDB format compatible entry.

Summary for 9KGR

• Entry DOI: 10.2210/pdb9kgr/pdb
• Descriptor: 3C-like proteinase nsp5, (S)-2-((R)-2-cyclopentyl-2-pivalamidoacetamido)-N-((2S,3R)-4-(cyclopropylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopiperidin-3-yl)butan-2-yl)pentanamide, cyclopropylcarbamic acid, ... (4 entities in total)
• Functional Keywords: protease, cov2, hydrolase, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Severe acute respiratory syndrome coronavirus 2; More
• Total number of polymer chains: 4
• Total formula weight: 69665.46

Authors

Baburajendran, N. (deposition date: 2024-11-08, release date: 2025-08-20, Last modification date: 2025-09-10)

Primary citation

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.,Liu, B.,Tan, S.T.,Kwek, P.Z.,Dawson, M.D.,Oh, Q.Y.,Koh, X.,Joy, J.,Lee, M.A.,Stunkel, W.,Pendharkar, V.,Hentze, H.,Lim, S.P.,Ethirajulu, K.,Brian Chia, C.S.,Cherian, J.
Discovery of an Orally Bioavailable Reversible Covalent SARS-CoV-2 M pro Inhibitor with Pan-Coronavirus Activity.
J.Med.Chem., 68:17087-17102, 2025

PubMed 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 M, a key viral protease, which led to the discovery of compound , a reversible covalent inhibitor with potent antiviral activity against several clinical variants of SARS-CoV-2. Compound demonstrated dose-dependent efficacy in a mouse-adapted SARS-CoV-2 infection model, with favorable pharmacokinetic profiles in mice, rats, dogs, and monkeys.

PubMed: 40773370
DOI: 10.1021/acs.jmedchem.5c00581

Experimental method

X-RAY DIFFRACTION (1.47 Å)