7JQ2

Structure of the SARS-CoV-2 main protease in complex with inhibitor MPI5

7JQ2 の概要

• エントリーDOI: 10.2210/pdb7jq2/pdb
• 分子名称: 3C-like proteinase, N-[(benzyloxy)carbonyl]-L-valyl-3-cyclohexyl-N-{(2S)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-L-alaninamide (3 entities in total)
• 機能のキーワード: covid-19, sars-cov-2, main protease, reversible covalent inhibitors, viral protein, hydrolase-inhibitor complex, hydrolase/inhibitor
• 由来する生物種: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV, SARS-CoV-2, COVID-19 virus)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34386.23

構造登録者

Yang, K.,Liu, W. (登録日: 2020-08-10, 公開日: 2020-12-23, 最終更新日: 2024-11-06)

主引用文献

Yang, K.S.,Ma, X.R.,Ma, Y.,Alugubelli, Y.R.,Scott, D.A.,Vatansever, E.C.,Drelich, A.K.,Sankaran, B.,Geng, Z.Z.,Blankenship, L.R.,Ward, H.E.,Sheng, Y.J.,Hsu, J.C.,Kratch, K.C.,Zhao, B.,Hayatshahi, H.S.,Liu, J.,Li, P.,Fierke, C.A.,Tseng, C.K.,Xu, S.,Liu, W.R.
A Quick Route to Multiple Highly Potent SARS-CoV-2 Main Protease Inhibitors*.
Chemmedchem, 16:942-948, 2021

PubMed Abstract: The COVID-19 pathogen, SARS-CoV-2, requires its main protease (SC2M ) to digest two of its translated long polypeptides to form a number of mature proteins that are essential for viral replication and pathogenesis. Inhibition of this vital proteolytic process is effective in preventing the virus from replicating in infected cells and therefore provides a potential COVID-19 treatment option. Guided by previous medicinal chemistry studies about SARS-CoV-1 main protease (SC1M ), we have designed and synthesized a series of SC2M inhibitors that contain β-(S-2-oxopyrrolidin-3-yl)-alaninal (Opal) for the formation of a reversible covalent bond with the SC2M active-site cysteine C145. All inhibitors display high potency with K values at or below 100 nM. The most potent compound, MPI3, has as a K value of 8.3 nM. Crystallographic analyses of SC2M bound to seven inhibitors indicated both formation of a covalent bond with C145 and structural rearrangement from the apoenzyme to accommodate the inhibitors. Virus inhibition assays revealed that several inhibitors have high potency in inhibiting the SARS-CoV-2-induced cytopathogenic effect in both Vero E6 and A549/ACE2 cells. Two inhibitors, MPI5 and MPI8, completely prevented the SARS-CoV-2-induced cytopathogenic effect in Vero E6 cells at 2.5-5 μM and A549/ACE2 cells at 0.16-0.31 μM. Their virus inhibition potency is much higher than that of some existing molecules that are under preclinical and clinical investigations for the treatment of COVID-19. Our study indicates that there is a large chemical space that needs to be explored for the development of SC2M inhibitors with ultra-high antiviral potency.

PubMed: 33283984
DOI: 10.1002/cmdc.202000924

実験手法

X-RAY DIFFRACTION (1.4 Å)