A cyclic peptide-grafted Fc with hepatocyte growth factor functionality ameliorates hepatic fibrosis in a non-alcoholic steatohepatitis mouse model
Nichole Marcela Rojas-Chaverra,
Ryu Imamura,
Hiroki Sato,
Toby Passioura,
Emiko Mihara,
Tatsunori Nishimura,
Junichi Takagi,
Hiroaki Suga,
Kunio Matsumoto,
Katsuya Sakai
Affiliations
Nichole Marcela Rojas-Chaverra
Division of Tumor Dynamics and Regulation, Cancer Research Institute, Kanazawa University, Kanazawa 920-1192, Japan
Ryu Imamura
Division of Tumor Dynamics and Regulation, Cancer Research Institute, Kanazawa University, Kanazawa 920-1192, Japan; WPI-Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, Kanazawa 920-1192, Japan
Hiroki Sato
Division of Tumor Dynamics and Regulation, Cancer Research Institute, Kanazawa University, Kanazawa 920-1192, Japan
Toby Passioura
School of Chemistry, School of Life and Environmental Sciences, and Sydney Analytical, The University of Sydney, Sydney NSW 2006, Australia; Department of Chemistry, Graduate School of Science, The University of Tokyo, Tokyo 113-0033, Japan
Emiko Mihara
Laboratory of Protein Synthesis and Expression, Institute for Protein Research, Osaka University, Suita 565-0871, Japan
Tatsunori Nishimura
Division of Cancer Biology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
Junichi Takagi
Laboratory of Protein Synthesis and Expression, Institute for Protein Research, Osaka University, Suita 565-0871, Japan
Hiroaki Suga
Department of Chemistry, Graduate School of Science, The University of Tokyo, Tokyo 113-0033, Japan
Kunio Matsumoto
Division of Tumor Dynamics and Regulation, Cancer Research Institute, Kanazawa University, Kanazawa 920-1192, Japan; WPI-Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, Kanazawa 920-1192, Japan
Katsuya Sakai
Division of Tumor Dynamics and Regulation, Cancer Research Institute, Kanazawa University, Kanazawa 920-1192, Japan; WPI-Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, Kanazawa 920-1192, Japan; Corresponding author
Summary: The regenerative functions associated with cytokines and growth factors have immense therapeutic potential; however, their poor pharmacokinetics, resulting from structural features, hinder their effectiveness. In this study, we aimed to enhance the pharmacokinetics of growth factors by designing receptor-binding macrocyclic peptides through in vitro mRNA display and grafting them into loops of immunoglobulin’s crystallizable region (Fc). As a model, we developed peptide-grafted Fc proteins with hepatocyte growth factor (HGF) functionality that exhibited a prolonged circulation half-life and could be administered subcutaneously. The Fc-based HGF mimetic alleviated liver fibrosis in a mouse model fed a choline-deficient high-fat diet, which induces hepatic features of non-alcoholic steatohepatitis, including fibrosis, showcasing its potential as a therapeutic intervention. This study provides a basis for developing growth factor and cytokine mimetics with improved pharmacokinetics, expanding their therapeutic applications.
