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

• DOI: 10.1073/pnas.2413465122
• Publication Date: 2025-01-24T17:46:16Z
• Authors: Shun Nakamura; Yukihiro Tanimura; Risa Nomura; Hiroshi Suzuki; Kouki Nishikawa; Akiko Kamegawa; Nobutaka Numoto; Atsushi Tanaka; Shigeru Kawabata; Shoichi Sakaguchi; Akino Emi; Youichi Suzuki; Yoshinori Fujiyoshi
• Keywords: Protein Engineering

Pathogen mutations present an inevitable and challenging problem for therapeutics the development of mutation-tolerant anti-infective drugs to strengthen global health combat evolving pathogens is urgently needed. While spike proteins on viral surfaces are attractive targets preventing entry, they mutate frequently, making it difficult develop effective therapeutics. Here, we used a structure-guided strategy engineer inhibitor peptide against SARS-CoV-2 spike, called CeSPIACE, with potent binding ability all variants enhance affinity invariant architecture receptor-binding domain (RBD). High-resolution structures complexed mutant RBDs revealed mechanism inhibition. CeSPIACE bound major picomolar inhibited infection by in VeroE6/TMPRSS2 cells (IC 50 4 pM 13 nM) demonstrated vivo efficacy inhalation administration hamsters. Mutagenesis analyses address mutation risks confirmed tolerance existing and/or potential future RBD. Our engineering inhibitors may be applicable other infectious diseases.