7X6K

SARS-CoV-2 3CL protease (3CLpro) in complex with compound 3w

Summary for 7X6K

• Entry DOI: 10.2210/pdb7x6k/pdb
• Descriptor: 3C-like proteinase, 1H-indole-2-carbaldehyde (3 entities in total)
• Functional Keywords: viral protein-inhibitor complex, viral protein/inhibitor
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 1
• Total formula weight: 33970.71

Authors

Su, H.,Nie, T.,Xie, H.,Li, Z.W.,Li, M.J.,Xu, Y. (deposition date: 2022-03-07, release date: 2022-07-06, Last modification date: 2023-11-29)

Primary citation

Pillaiyar, T.,Flury, P.,Kruger, N.,Su, H.,Schakel, L.,Barbosa Da Silva, E.,Eppler, O.,Kronenberger, T.,Nie, T.,Luedtke, S.,Rocha, C.,Sylvester, K.,Petry, M.R.I.,McKerrow, J.H.,Poso, A.,Pohlmann, S.,Gutschow, M.,O'Donoghue, A.J.,Xu, Y.,Muller, C.E.,Laufer, S.A.
Small-Molecule Thioesters as SARS-CoV-2 Main Protease Inhibitors: Enzyme Inhibition, Structure-Activity Relationships, Antiviral Activity, and X-ray Structure Determination.
J.Med.Chem., 65:9376-9395, 2022

PubMed Abstract: The main protease (M, 3CL) of SARS-CoV-2 is an attractive target in coronaviruses because of its crucial involvement in viral replication and transcription. Here, we report on the design, synthesis, and structure-activity relationships of novel small-molecule thioesters as SARS-CoV-2 M inhibitors. Compounds and exhibited excellent SARS-CoV-2 M inhibition with / of 58,700 M s ( = 0.0141 μM) and 27,200 M s ( = 0.0332 μM), respectively. In Calu-3 and Vero76 cells, compounds , , , , , and displayed antiviral activity in the nanomolar range without host cell toxicity. Co-crystallization of and with SARS-CoV-2 M was accomplished, and the X-ray structures showed covalent binding with the catalytic Cys145 residue of the protease. The potent SARS-CoV-2 Mpro inhibitors also inhibited the M of other beta-coronaviruses, including SARS-CoV-1 and MERS-CoV, indicating that they might be useful to treat a broader range of coronaviral infections.

PubMed: 35709506
DOI: 10.1021/acs.jmedchem.2c00636

Experimental method

X-RAY DIFFRACTION (2.34 Å)