9MBV

Crystal structure of SARS main protease complex with CCF0058981

Summary for 9MBV

• Entry DOI: 10.2210/pdb9mbv/pdb
• Descriptor: 3C-like proteinase nsp5, 2-(benzotriazol-1-yl)-~{N}-[(3-chlorophenyl)methyl]-~{N}-[4-(1~{H}-imidazol-5-yl)phenyl]ethanamide (3 entities in total)
• Functional Keywords: viral protein-inhibitor complex, viral protein
• Biological source: Severe acute respiratory syndrome-related coronavirus
• Total number of polymer chains: 2
• Total formula weight: 67225.59

Authors

Zeng, P.,Li, J. (deposition date: 2025-03-17, release date: 2026-01-21, Last modification date: 2026-02-04)

Primary citation

Zeng, P.,Zhou, X.,Guo, L.,Li, W.,Li, J.
Structural insights of the coronavirus main protease in complex with the non-covalent inhibitor CCF0058981.
J Struct Biol X, 13:100143-100143, 2026

PubMed Abstract: The highly pathogenic SARS-CoV-2 causes COVID-19, which threatens global public health and socio-economic stability through persistent transmission and mutation. Effective therapeutics against SARS-CoV-2 and its variants are urgently needed. The main protease (M), highly conserved among coronaviruses and lacking human homologs, is pivotal for viral replication, making it an attractive antiviral target. CCF0058981, a novel non-covalent inhibitor developed based on the ML300 scaffold, demonstrates potent low-nanomolar inhibitory activity against SARS-CoV-2 M and sub-micromolar antiviral efficacy against SARS-CoV-2. Its non-covalent binding mechanism effectively mitigates the off-target risks commonly associated with traditional covalent inhibitors, thereby providing a versatile scaffold for the development of highly safe and effective anti-coronavirus therapeutics. However, the structural basis underlying CCF0058981's inhibitory mechanism against SARS-CoV-2 M remains to be elucidated. Here, we report for the first time two crystal structures of M from SARS-CoV-2 and SARS-CoV in complex with the inhibitor CCF0058981. Detailed crystal structure analysis reveals that CCF0058981 occupies the catalytic pocket of M via conserved hydrogen bonds and hydrophobic interactions. The superimposition analysis of the reported crystal structures also reveals that CCF0058981 maintains stable binding to the M mutants (M49I and V186F), demonstrating its potential to combat drug resistance, demonstrating its potential to counteract drug resistance. Molecular dynamics simulations further validate the stability of the inhibitor-protease complex. These findings provide mechanistic insights into CCF0058981's inhibition and support developing broad-spectrum coronavirus therapeutics.

PubMed: 41567121
DOI: 10.1016/j.yjsbx.2026.100143

Experimental method

X-RAY DIFFRACTION (1.94 Å)