9EXA

SARS-CoV-2 M protein dimer (short form) in complex with Fab-B and CIM-834

This is a non-PDB format compatible entry.

Summary for 9EXA

• Entry DOI: 10.2210/pdb9exa/pdb
• EMDB information: 50034
• Descriptor: Membrane protein, Fab-B light chain, Fab-B heavy chain, ... (4 entities in total)
• Functional Keywords: inhibitor, complex, membrane protein, antibody, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2; More
• Total number of polymer chains: 6
• Total formula weight: 137766.26

Authors

Debski-Antoniak, O.J.,Hurdiss, D.L. (deposition date: 2024-04-05, release date: 2025-01-22, Last modification date: 2025-04-16)

Primary citation

Laporte, M.,Jochmans, D.,Bardiot, D.,Desmarets, L.,Debski-Antoniak, O.J.,Mizzon, G.,Abdelnabi, R.,Leyssen, P.,Chiu, W.,Zhang, Z.,Nomura, N.,Boland, S.,Ohto, U.,Stahl, Y.,Wuyts, J.,De Jonghe, S.,Stevaert, A.,van Hemert, M.J.,Bontes, B.W.,Wanningen, P.,Groenewold, G.J.M.,Zegar, A.,Owczarek, K.,Joshi, S.,Koukni, M.,Arzel, P.,Klaassen, H.,Vanherck, J.C.,Vandecaetsbeek, I.,Cremers, N.,Donckers, K.,Francken, T.,Van Buyten, T.,Rymenants, J.,Schepers, J.,Pyrc, K.,Hilgenfeld, R.,Dubuisson, J.,Bosch, B.J.,Van Kuppeveld, F.,Eydoux, C.,Decroly, E.,Canard, B.,Naesens, L.,Weynand, B.,Snijder, E.J.,Belouzard, S.,Shimizu, T.,Bartenschlager, R.,Hurdiss, D.L.,Marchand, A.,Chaltin, P.,Neyts, J.
A coronavirus assembly inhibitor that targets the viral membrane protein.
Nature, 640:514-523, 2025

PubMed Abstract: The coronavirus membrane protein (M) is the main organizer of coronavirus assembly. Here, we report on an M-targeting molecule, CIM-834, that blocks the assembly of SARS-CoV-2. CIM-834 was obtained through high-throughput phenotypic antiviral screening followed by medicinal-chemistry efforts and target elucidation. CIM-834 inhibits the replication of SARS-CoV-2 (including a broad panel of variants) and SARS-CoV. In SCID mice and Syrian hamsters intranasally infected with SARS-CoV-2, oral treatment reduced lung viral titres to nearly undetectable levels, even (as shown in mice) when treatment was delayed until 24 h before the end point. Treatment of infected hamsters prevented transmission to untreated sentinels. Transmission electron microscopy studies show that virion assembly is completely absent in cells treated with CIM-834. Single-particle cryo-electron microscopy reveals that CIM-834 binds and stabilizes the M protein in its short form, thereby preventing the conformational switch to the long form, which is required for successful particle assembly. In conclusion, we have discovered a new druggable target in the replication cycle of coronaviruses and a small molecule that potently inhibits it.

PubMed: 40140569
DOI: 10.1038/s41586-025-08773-x

Experimental method

ELECTRON MICROSCOPY (3.2 Å)