Structure- guided engineering of a mutation- tolerant inhibitor peptide against variable SARS- CoV-2 spikes

• 成果类型: Article
• 署名作者: Nakamura, Shun; Tanimura, Yukihiro; Nomura, Risa; Suzuki, Hiroshi; Nishikawa, Kouki; Kamegawa, Akiko; Numoto, Nobutaka; Tanaka, Atsushi; Kawabata, Shigeru; Sakaguchi, Shoichi; Emi, Akino; Suzuki, Youichi; Fujiyoshi, Yoshinori
• 署名单位: Okayama University; Osaka Medical & Pharmaceutical University; Osaka Medical & Pharmaceutical University; Osaka Medical & Pharmaceutical University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12487
• DOI: 10.1073/pnas.2413465122
• 发表日期: 2025-01-28
• 关键词: sars-cov-2; CORONAVIRUS; infection

摘要

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 (IC50 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.