De novo peptide grafting to a self-assembling nanocapsule yields a hepatocyte growth factor receptor agonist
Yamato Komatsu,
Naohiro Terasaka,
Katsuya Sakai,
Emiko Mihara,
Risa Wakabayashi,
Kunio Matsumoto,
Donald Hilvert,
Junichi Takagi,
Hiroaki Suga
Affiliations
Yamato Komatsu
Department of Chemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Naohiro Terasaka
Department of Chemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; Corresponding author
Katsuya Sakai
Division of Tumor Dynamics and Regulation, Cancer Research Institute, and WPI-Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, Kakuma, Kanazawa-shi, Ishikawa 920-1192, Japan
Emiko Mihara
Laboratory of Protein Synthesis and Expression, Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita-shi, Osaka 565-0871, Japan
Risa Wakabayashi
Department of Chemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Kunio Matsumoto
Division of Tumor Dynamics and Regulation, Cancer Research Institute, and WPI-Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, Kakuma, Kanazawa-shi, Ishikawa 920-1192, Japan
Donald Hilvert
Laboratory of Organic Chemistry, ETH Zürich, 8093 Zürich, Switzerland
Junichi Takagi
Laboratory of Protein Synthesis and Expression, Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita-shi, Osaka 565-0871, Japan
Hiroaki Suga
Department of Chemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; Corresponding author
Summary: Lasso-grafting (LG) technology is a method for generating de novo biologics (neobiologics) by genetically implanting macrocyclic peptide pharmacophores, which are selected in vitro against a protein of interest, into loops of arbitrary protein scaffolds. In this study, we have generated a neo-capsid that potently binds the hepatocyte growth factor receptor MET by LG of anti-MET peptide pharmacophores into a circularly permuted variant of Aquifex aeolicus lumazine synthase (AaLS), a self-assembling protein nanocapsule. By virtue of displaying multiple-pharmacophores on its surface, the neo-capsid can induce dimerization (or multimerization) of MET, resulting in phosphorylation and endosomal internalization of the MET-capsid complex. This work demonstrates the potential of the LG technology as a synthetic biology approach for generating capsid-based neobiologics capable of activating signaling receptors.
