8RJZ

Crystal structure of SARS-CoV-2 main protease (MPro) in complex with the non-covalent inhibitor GUE-3801 (compound 80 in publication)

This is a non-PDB format compatible entry.

Summary for 8RJZ

• Entry DOI: 10.2210/pdb8rjz/pdb
• Descriptor: 3C-like proteinase nsp5, (7~{S})-6-[2-[2,4-bis(chloranyl)phenoxy]ethanoyl]-14-fluoranyl-10-(iminomethyl)-9-methyl-7-(phenylmethyl)-2-oxa-6,9,10-triazabicyclo[10.4.0]hexadeca-1(12),13,15-trien-8-one, 2-[3-(2-HYDROXY-1,1-DIHYDROXYMETHYL-ETHYLAMINO)-PROPYLAMINO]-2-HYDROXYMETHYL-PROPANE-1,3-DIOL, ... (5 entities in total)
• Functional Keywords: mpro, main protease, inhibitor, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 2
• Total formula weight: 69461.61

Authors

Strater, N.,Claff, T.,Sylvester, K.,Mueller, C.E.,Guetschow, M.,Useini, A. (deposition date: 2023-12-22, release date: 2024-05-29, Last modification date: 2024-10-16)

Primary citation

Breidenbach, J.,Voget, R.,Si, Y.,Hingst, A.,Claff, T.,Sylvester, K.,Wolf, V.,Krasniqi, V.,Useini, A.,Strater, N.,Ogura, Y.,Kawaguchi, A.,Muller, C.E.,Gutschow, M.
Macrocyclic Azapeptide Nitriles: Structure-Based Discovery of Potent SARS-CoV-2 Main Protease Inhibitors as Antiviral Drugs.
J.Med.Chem., 67:8757-8790, 2024

PubMed Abstract: Given the crucial role of the main protease (M) in the replication cycle of SARS-CoV-2, this viral cysteine protease constitutes a high-profile drug target. We investigated peptidomimetic azapeptide nitriles as auspicious, irreversibly acting inhibitors of M. Our systematic approach combined an M active-site scanning by combinatorially assembled azanitriles with structure-based design. Encouraged by the bioactive conformation of open-chain inhibitors, we conceptualized the novel chemotype of macrocyclic azanitriles whose binding mode was elucidated by cocrystallization. This strategy provided a favorable entropic contribution to target binding and resulted in the development of the extraordinarily potent M inhibitor with an IC value of 3.23 nM and a second-order rate constant of inactivation, /, of 448,000 Ms. The open-chain M inhibitor , along with the macrocyclic compounds and , a broad-spectrum anticoronaviral agent, demonstrated the highest antiviral activity with EC values in the single-digit micromolar range. Our findings are expected to promote the future development of peptidomimetic M inhibitors as anti-SARS-CoV-2 agents.

PubMed: 38753594
DOI: 10.1021/acs.jmedchem.4c00053

Experimental method

X-RAY DIFFRACTION (1.7 Å)