7M2P

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

7M2P の概要

• エントリーDOI: 10.2210/pdb7m2p/pdb
• 関連するBIRD辞書のPRD_ID: PRD_002469
• 分子名称: 3C-like proteinase, Inhibitor 18 in bound form (3 entities in total)
• 機能のキーワード: covid-19, sars-cov-2, 3cl protease, aldehyde inhibitor, viral protein-hydrolase inhibitor complex, viral protein/hydrolase inhibitor
• 由来する生物種: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV, SARS-CoV-2, COVID-19 virus); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 34396.22

構造登録者

Yang, K.,Li, L. (登録日: 2021-03-17, 公開日: 2021-08-25, 最終更新日: 2024-11-13)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.7 Å)