7M2P

Structure of the SARS-CoV-2 3CL protease in complex with inhibitor 18

Summary for 7M2P

• Entry DOI: 10.2210/pdb7m2p/pdb
• Related PRD ID: PRD_002469
• Descriptor: 3C-like proteinase, Inhibitor 18 in bound form (3 entities in total)
• Functional Keywords: covid-19, sars-cov-2, 3cl protease, aldehyde inhibitor, viral protein-hydrolase inhibitor complex, viral protein/hydrolase inhibitor
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV, SARS-CoV-2, COVID-19 virus); More
• Total number of polymer chains: 2
• Total formula weight: 34396.22

Authors

Yang, K.,Li, L. (deposition date: 2021-03-17, release date: 2021-08-25, Last modification date: 2024-11-13)

Primary citation

Li, L.,Chenna, B.C.,Yang, K.S.,Cole, T.R.,Goodall, Z.T.,Giardini, M.,Moghadamchargari, Z.,Hernandez, E.A.,Gomez, J.,Calvet, C.M.,Bernatchez, J.A.,Mellott, D.M.,Zhu, J.,Rademacher, A.,Thomas, D.,Blankenship, L.R.,Drelich, A.,Laganowsky, A.,Tseng, C.K.,Liu, W.R.,Wand, A.J.,Cruz-Reyes, J.,Siqueira-Neto, J.L.,Meek, T.D.
Self-Masked Aldehyde Inhibitors: A Novel Strategy for Inhibiting Cysteine Proteases.
J.Med.Chem., 64:11267-11287, 2021

PubMed Abstract: Cysteine proteases comprise an important class of drug targets, especially for infectious diseases such as Chagas disease (cruzain) and COVID-19 (3CL protease, cathepsin L). Peptide aldehydes have proven to be potent inhibitors for all of these proteases. However, the intrinsic, high electrophilicity of the aldehyde group is associated with safety concerns and metabolic instability, limiting the use of aldehyde inhibitors as drugs. We have developed a novel class of self-masked aldehyde inhibitors (SMAIs) for cruzain, the major cysteine protease of the causative agent of Chagas disease-. These SMAIs exerted potent, reversible inhibition of cruzain (* = 18-350 nM) while apparently protecting the free aldehyde in cell-based assays. We synthesized prodrugs of the SMAIs that could potentially improve their pharmacokinetic properties. We also elucidated the kinetic and chemical mechanism of SMAIs and applied this strategy to the design of anti-SARS-CoV-2 inhibitors.

PubMed: 34288674
DOI: 10.1021/acs.jmedchem.1c00628

Experimental method

X-RAY DIFFRACTION (1.7 Å)