9GV2

Crystal structure of SARS-CoV-2 main protease (MPro) in complex with the covalently bound inhibitor FP237 (compound 8p in publication)

This is a non-PDB format compatible entry.

Summary for 9GV2

• Entry DOI: 10.2210/pdb9gv2/pdb
• Descriptor: 3C-like proteinase nsp5, (2S)-2-[2-(3-methoxyphenoxy)ethanoylamino]-4-methyl-N-[(2S)-3-oxidanylidene-1-phenyl-pentan-2-yl]pentanamide, DIMETHYL SULFOXIDE, ... (8 entities in total)
• Functional Keywords: protease, inhibitor, dipeptidyl inhibitors, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 2
• Total formula weight: 69231.81

Authors

Strater, N.,Sylvester, K.,Muller, C.E.,Flury, P.,Kruger, N.,Breidenbach, J.,Guetschow, M.,Laufer, S.A.,Pillaiyar, T. (deposition date: 2024-09-20, release date: 2025-01-29, Last modification date: 2025-02-26)

Primary citation

Flury, P.,Kruger, N.,Sylvester, K.,Breidenbach, J.,Al Hamwi, G.,Qiao, J.,Chen, Y.,Rocha, C.,Serafim, M.S.M.,Barbosa da Silva, E.,Pohlmann, S.,Poso, A.,Kronenberger, T.,Rox, K.,O'Donoghue, A.J.,Yang, S.,Strater, N.,Gutschow, M.,Laufer, S.A.,Muller, C.E.,Pillaiyar, T.
Design, Synthesis, and Unprecedented Interactions of Covalent Dipeptide-Based Inhibitors of SARS-CoV-2 Main Protease and Its Variants Displaying Potent Antiviral Activity.
J.Med.Chem., 68:3626-3652, 2025

PubMed Abstract: The main protease (M) of SARS-CoV-2 is a key drug target for the development of antiviral therapeutics. Here, we designed and synthesized a series of small-molecule peptidomimetics with various cysteine-reactive electrophiles. Several compounds were identified as potent SARS-CoV-2 M inhibitors, including compounds (IC = 0.0752 μM), (IC = 0.0887 μM), (IC = 0.0199 μM), (IC = 0.0376 μM), (IC = 0.0177 μM), and (IC = 0.0130 μM). Most of them additionally inhibited cathepsin L and were also active against SARS-CoV-1 and MERS-CoV M. In Calu-3 cells, several inhibitors, including , , and , displayed high antiviral activity in the nanomolar range without showing cellular toxicity. The cocrystal structure of SARS-CoV-2 M in complex with revealed covalent binding to the enzyme's catalytic residue Cys145 and showed specific, unprecedented interactions within the substrate binding pocket. Compounds and especially were effective against a panel of naturally occurring nirmatrelvir-resistant mutants, particularly E166V, and showed metabolic stability and additional favorable pharmacokinetic properties, making it a suitable candidate for further preclinical development.

PubMed: 39813204
DOI: 10.1021/acs.jmedchem.4c02254

Experimental method

X-RAY DIFFRACTION (2.56 Å)