Structure-guided engineering of a mutation-tolerant inhibitor peptide against variable SARS-CoV-2 spikes
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 50 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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (13)
Shun Nakamura
Yukihiro Tanimura
Cellular and Structural Physiology Laboratory, Advanced Research Initiative, Institute of Integrated Research, Institute of Science Tokyo
Risa Nomura
Cellular and Structural Physiology Laboratory, Advanced Research Initiative, Institute of Integrated Research, Institute of Science Tokyo
Hiroshi Suzuki
Department of Polymer Chemistry, Graduate School of Engineering
Kouki Nishikawa
CeSPIA Inc., Taisei Otemachi
Akiko Kamegawa
Cellular and Structural Physiology Laboratory, Advanced Research Initiative, Institute of Integrated Research, Institute of Science Tokyo
Nobutaka Numoto
International Center for Structural Biology, Research Institute for Interdisciplinary Science, Okayama University
Atsushi Tanaka
Division of Research Animal Laboratory and Translational Medicine, Research and Development Center, Osaka Medical and Pharmaceutical University
Shigeru Kawabata
Department of Pathology, Faculty of Medicine, Osaka Medical and Pharmaceutical University
Shoichi Sakaguchi
Department of Microbiology and Infection Control, Faculty of Medicine, Osaka Medical and Pharmaceutical University
Akino Emi
Department of Microbiology and Infection Control, Faculty of Medicine, Osaka Medical and Pharmaceutical University
Youichi Suzuki
Department of Microbiology and Infection Control, Faculty of Medicine, Osaka Medical and Pharmaceutical University
Yoshinori Fujiyoshi
Cellular and Structural Physiology Laboratory, Advanced Research Initiative, Institute of Integrated Research, Institute of Science Tokyo