8GXH

The crystal structure of SARS-CoV-2 main protease in complex with 14b

8GXH の概要

• エントリーDOI: 10.2210/pdb8gxh/pdb
• 分子名称: 3C-like proteinase nsp5, N-[(2S)-3-cyclohexyl-1-oxidanylidene-1-[[(2S,3R)-3-oxidanyl-4-oxidanylidene-1-[(3S)-2-oxidanylidenepiperidin-3-yl]-4-[(phenylmethyl)amino]butan-2-yl]amino]propan-2-yl]-1-benzofuran-2-carboxamide (3 entities in total)
• 機能のキーワード: sars-cov-2, main protease, 3clpro, mpro, viral protease, 14b, hydrolase
• 由来する生物種: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV, SARS-CoV-2)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34428.27

構造登録者

Zhao, Y.,Zhao, J.,Shao, M.,Yang, H.,Rao, Z. (登録日: 2022-09-20, 公開日: 2023-09-27, 最終更新日: 2024-10-23)

主引用文献

Xie, X.,Lan, Q.,Zhao, J.,Zhang, S.,Liu, L.,Zhang, Y.,Xu, W.,Shao, M.,Peng, J.,Xia, S.,Zhu, Y.,Zhang, K.,Zhang, X.,Zhang, R.,Li, J.,Dai, W.,Ge, Z.,Hu, S.,Yu, C.,Wang, J.,Ma, D.,Zheng, M.,Yang, H.,Xiao, G.,Rao, Z.,Lu, L.,Zhang, L.,Bai, F.,Zhao, Y.,Jiang, S.,Liu, H.
Structure-based design of pan-coronavirus inhibitors targeting host cathepsin L and calpain-1.
Signal Transduct Target Ther, 9:54-54, 2024

PubMed Abstract: Respiratory disease caused by coronavirus infection remains a global health crisis. Although several SARS-CoV-2-specific vaccines and direct-acting antivirals are available, their efficacy on emerging coronaviruses in the future, including SARS-CoV-2 variants, might be compromised. Host-targeting antivirals provide preventive and therapeutic strategies to overcome resistance and manage future outbreak of emerging coronaviruses. Cathepsin L (CTSL) and calpain-1 (CAPN1) are host cysteine proteases which play crucial roles in coronaviral entrance into cells and infection-related immune response. Here, two peptidomimetic α-ketoamide compounds, 14a and 14b, were identified as potent dual target inhibitors against CTSL and CAPN1. The X-ray crystal structures of human CTSL and CAPN1 in complex with 14a and 14b revealed the covalent binding of α-ketoamide groups of 14a and 14b to C25 of CTSL and C115 of CAPN1. Both showed potent and broad-spectrum anticoronaviral activities in vitro, and it is worth noting that they exhibited low nanomolar potency against SARS-CoV-2 and its variants of concern (VOCs) with EC values ranging from 0.80 to 161.7 nM in various cells. Preliminary mechanistic exploration indicated that they exhibited anticoronaviral activity through blocking viral entrance. Moreover, 14a and 14b exhibited good oral pharmacokinetic properties in mice, rats and dogs, and favorable safety in mice. In addition, both 14a and 14b treatments demonstrated potent antiviral potency against SARS-CoV-2 XBB 1.16 variant infection in a K18-hACE2 transgenic mouse model. And 14b also showed effective antiviral activity against HCoV-OC43 infection in a mouse model with a final survival rate of 60%. Further evaluation showed that 14a and 14b exhibited excellent anti-inflammatory effects in Raw 264.7 mouse macrophages and in mice with acute pneumonia. Taken together, these results suggested that 14a and 14b are promising drug candidates, providing novel insight into developing pan-coronavirus inhibitors with antiviral and anti-inflammatory properties.

PubMed: 38443334
DOI: 10.1038/s41392-024-01758-8

実験手法

X-RAY DIFFRACTION (1.59 Å)