8YDV

Crystal structure of the receptor binding domain of SARS-CoV-2 Omicron BA.5 variant spike protein in complex with CeSPIACE

8YDV の概要

• エントリーDOI: 10.2210/pdb8ydv/pdb
• 分子名称: SARS-CoV-2 inhibiting peptide CeSPIACE, Spike protein S1, GLYCEROL, ... (4 entities in total)
• 機能のキーワード: rbd, viral protein-inhibitor complex, viral protein/inhibitor
• 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: 4
• 化学式量合計: 62814.35

構造登録者

Nakamura, S.,Numoto, N.,Fujiyoshi, Y. (登録日: 2024-02-21, 公開日: 2025-01-15, 最終更新日: 2025-07-30)

主引用文献

Nakamura, S.,Tanimura, Y.,Nomura, R.,Suzuki, H.,Nishikawa, K.,Kamegawa, A.,Numoto, N.,Tanaka, A.,Kawabata, S.,Sakaguchi, S.,Emi, A.,Suzuki, Y.,Fujiyoshi, Y.
Structure-guided engineering of a mutation-tolerant inhibitor peptide against variable SARS-CoV-2 spikes.
Proc.Natl.Acad.Sci.USA, 122:e2413465122-e2413465122, 2025

PubMed Abstract: Pathogen mutations present an inevitable and challenging problem for therapeutics and the development of mutation-tolerant anti-infective drugs to strengthen global health and combat evolving pathogens is urgently needed. While spike proteins on viral surfaces are attractive targets for preventing viral entry, they mutate frequently, making it difficult to develop effective therapeutics. Here, we used a structure-guided strategy to engineer an inhibitor peptide against the SARS-CoV-2 spike, called CeSPIACE, with mutation-tolerant and potent binding ability against all variants to enhance affinity for the invariant architecture of the receptor-binding domain (RBD). High-resolution structures of the peptide complexed with mutant RBDs revealed a mechanism of mutation-tolerant inhibition. CeSPIACE bound major mutant RBDs with picomolar affinity and inhibited infection by SARS-CoV-2 variants in VeroE6/TMPRSS2 cells (IC 4 pM to 13 nM) and demonstrated potent in vivo efficacy by inhalation administration in hamsters. Mutagenesis analyses to address mutation risks confirmed tolerance against existing and/or potential future mutations of the RBD. Our strategy of engineering mutation-tolerant inhibitors may be applicable to other infectious diseases.

PubMed: 39854234
DOI: 10.1073/pnas.2413465122

実験手法

X-RAY DIFFRACTION (2.2 Å)