8W2E

SARS-CoV-2 M protein dimer in complex with JNJ-9676 and Fab-B

This is a non-PDB format compatible entry.

Summary for 8W2E

• Entry DOI: 10.2210/pdb8w2e/pdb
• EMDB information: 43745
• Descriptor: Membrane protein, Fab B Heavy Chain, Fab B Light Chain, ... (4 entities in total)
• Functional Keywords: sars-cov-2, m protein, inhibitor bound complex, viral protein-immune system complex, viral protein/immune system
• Biological source: SARS-CoV-2 pseudovirus; More
• Total number of polymer chains: 6
• Total formula weight: 157687.37

Authors

Yin, Y.,Van Damme, E. (deposition date: 2024-02-20, release date: 2025-01-29, Last modification date: 2025-04-23)

Primary citation

Van Damme, E.,Abeywickrema, P.,Yin, Y.,Xie, J.,Jacobs, S.,Mann, M.K.,Doijen, J.,Miller, R.,Piassek, M.,Marsili, S.,Subramanian, M.,Gottlieb, L.,Abdelnabi, R.,Van Gool, M.,Van den Broeck, N.,De Pauw, I.,Diels, A.,Vermeulen, P.,Temmerman, K.,Scobey, T.,Mattocks, M.,Schafer, A.,Jochmans, D.,De Jonghe, S.,Leyssen, P.,Chiu, W.,Diosa Toro, M.,Zwaagstra, M.,Leijs, A.A.,De Gruyter, H.L.M.,Buyck, C.,Van Den Heede, K.,Jacobs, F.,Van den Eynde, C.,Thijs, L.,Raeymaekers, V.,Miller, S.,Del Rosario, A.,Neyts, J.,Peeters, D.,Baric, R.S.,van Kuppeveld, F.J.M.,Snijder, E.J.,van Hemert, M.J.,Monshouwer, M.,Sharma, S.,Draghia-Akli, R.,Koul, A.,Van Loock, M.
A small-molecule SARS-CoV-2 inhibitor targeting the membrane protein.
Nature, 640:506-513, 2025

PubMed Abstract: The membrane (M) protein of betacoronaviruses is well conserved and has a key role in viral assembly. Here we describe the identification of JNJ-9676, a small-molecule inhibitor targeting the coronavirus M protein. JNJ-9676 demonstrates in vitro nanomolar antiviral activity against SARS-CoV-2, SARS-CoV and sarbecovirus strains from bat and pangolin zoonotic origin. Using cryogenic electron microscopy (cryo-EM), we determined a binding pocket of JNJ-9676 formed by the transmembrane domains of the M protein dimer. Compound binding stabilized the M protein dimer in an altered conformational state between its long and short forms, preventing the release of infectious virus. In a pre-exposure Syrian golden hamster model, JNJ-9676 (25 mg per kg twice per day) showed excellent efficacy, illustrated by a significant reduction in viral load and infectious virus in the lung by 3.5 and 4 log-transformed RNA copies and 50% tissue culture infective dose (TCID) per mg lung, respectively. Histopathology scores at this dose were reduced to the baseline. In a post-exposure hamster model, JNJ-9676 was efficacious at 75 mg per kg twice per day even when added at 48 h after infection, when peak viral loads were observed. The M protein is an attractive antiviral target to block coronavirus replication, and JNJ-9676 represents an interesting chemical series towards identifying clinical candidates addressing the current and future coronavirus pandemics.

PubMed: 40140563
DOI: 10.1038/s41586-025-08651-6

Experimental method

ELECTRON MICROSCOPY (3.06 Å)