7ZV5

Crystal structure of SARS Cov-2 main protease in complex with an inhibitor 4

7ZV5 の概要

• エントリーDOI: 10.2210/pdb7zv5/pdb
• 関連するBIRD辞書のPRD_ID: PRD_002413
• 分子名称: 3C-like proteinase nsp5, inhibitor TRIP5, DIMETHYL SULFOXIDE, ... (4 entities in total)
• 機能のキーワード: sars cov-2, 3cl, main protease, antiviral protein
• 由来する生物種: Severe acute respiratory syndrome coronavirus 2; 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 34352.24

構造登録者

Rahimova, R.,Di Micco, S.,Marquez, J.A. (登録日: 2022-05-13, 公開日: 2022-11-30, 最終更新日: 2024-01-31)

主引用文献

Di Micco, S.,Rahimova, R.,Sala, M.,Scala, M.C.,Vivenzio, G.,Musella, S.,Andrei, G.,Remans, K.,Mammri, L.,Snoeck, R.,Bifulco, G.,Di Matteo, F.,Vestuto, V.,Campiglia, P.,Marquez, J.A.,Fasano, A.
Rational design of the zonulin inhibitor AT1001 derivatives as potential anti SARS-CoV-2.
Eur.J.Med.Chem., 244:114857-114857, 2022

PubMed Abstract: Although vaccines are greatly mitigating the worldwide pandemic diffusion of SARS-Cov-2, therapeutics should provide many distinct advantages as complementary approach to control the viral spreading. Here, we report the development of new tripeptide derivatives of AT1001 against SARS-CoV-2 M. By molecular modeling, a small compound library was rationally designed and filtered for enzymatic inhibition through FRET assay, leading to the identification of compound 4. X-ray crystallography studies provide insights into its binding mode and confirm the formation of a covalent bond with M C145. In vitro antiviral tests indicate the improvement of biological activity of 4 respect to AT1001. In silico and X-ray crystallography analysis led to 58, showing a promising activity against three SARS-CoV-2 variants and a valuable safety in Vero cells and human embryonic lung fibroblasts. The drug tolerance was also confirmed by in vivo studies, along with pharmacokinetics evaluation. In summary, 58 could pave the way to develop a clinical candidate for intranasal administration.

PubMed: 36332548
DOI: 10.1016/j.ejmech.2022.114857

実験手法

X-RAY DIFFRACTION (1.999 Å)