9MVO

Crystal Structure of SARS-CoV-2 Main Protease (Mpro) in Complex with Inhibitor AVI-4692

This is a non-PDB format compatible entry.

Summary for 9MVO

• Entry DOI: 10.2210/pdb9mvo/pdb
• Descriptor: 3C-like proteinase nsp5, (3M,5P,6M)-5-(1H-1,2,3-benzotriazol-1-yl)-6-(3-chlorophenyl)-3-(isoquinolin-4-yl)-1-(prop-2-en-1-yl)pyrimidine-2,4(1H,3H)-dione, (3M,5P,6M)-5-(1H-1,2,3-benzotriazol-1-yl)-6-(3-chlorophenyl)-3-(isoquinolin-4-yl)-1-(prop-2-yn-1-yl)pyrimidine-2,4(1H,3H)-dione, ... (4 entities in total)
• Functional Keywords: sars-cov-2 main protease sars-cov-2 mpro main protease mpro, hydrolase
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 1
• Total formula weight: 34725.29

Authors

Diallo, A.,Gumpena, R.,Verba, K. (deposition date: 2025-01-15, release date: 2025-07-23, Last modification date: 2025-08-13)

Primary citation

Detomasi, T.C.,Degotte, G.,Huang, S.,Suryawanshi, R.K.,Diallo, A.,Lizzadro, L.,Zapatero-Belinchon, F.J.,Taha, T.Y.,Li, J.,Richards, A.L.,Hantz, E.R.,Alam, Z.,Montano, M.,McCavitt-Malvido, M.,Gumpena, R.,Partridge, J.R.,Correy, G.J.,Matsui, Y.,Charvat, A.F.,Glenn, I.S.,Rosecrans, J.,Revalde, J.L.,Anderson, D.,Hultquist, J.F.,Arkin, M.R.,Neitz, R.J.,Swaney, D.L.,Krogan, N.J.,Shoichet, B.K.,Verba, K.A.,Ott, M.,Renslo, A.R.,Craik, C.S.
Structure-based discovery of highly bioavailable, covalent, broad-spectrum coronavirus M Pro inhibitors with potent in vivo efficacy.
Sci Adv, 11:eadt7836-eadt7836, 2025

PubMed Abstract: The main protease (M) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a validated drug target. Starting with a lead-like dihydrouracil chemotype identified in a large-library docking campaign, we improved M inhibition >1000-fold by engaging additional M subsites and using a latent electrophile to engage Cys. Advanced leads from this series show pan-coronavirus antiviral activity, low clearance in mice, and for , a rapid reduction in viral titers >1,000,000 after just three doses. Both compounds are well distributed in mouse tissues, including brain, where concentrations >1000× the 90% effective concentration are observed 8 hours after oral dosing for . shows minimal inhibition of major cytochrome P450s and human proteases. also exhibits synergy with the RNA-dependent RNA polymerase inhibitor, molnupiravir, in cellular infection models. Related analogs strongly inhibit nirmatrelvir-resistant M mutant virus. The properties of this chemotype are differentiated from existing clinical and preclinical M inhibitors and will advance therapeutic development against emerging SARS-CoV-2 variants and other coronaviruses.

PubMed: 40267184
DOI: 10.1126/sciadv.adt7836

Experimental method

X-RAY DIFFRACTION (1.84 Å)