image: HGF mimetic molecule was developed by grafting the newly identified c-Met receptor-binding cyclic peptides (A) into the loop structures of immunoglobulin Fc (B).
Credit: 2024 Rojas-Chaverra, et al. Published by Elsevier Inc.
A research group led by Associate Professor Katsuya Sakai, Researcher Nichole Marcela Rojas-Chaverra, and Professor Kunio Matsumoto of the Cancer Research Institute and Nano-Life Science (WPI-NanoLSI) at Kanazawa University has developed a long-acting, subcutaneously injectable artificial hepatocyte growth factor (HGF) mimetic molecule using a fusion technology of cyclic peptides and protein engineering. They demonstrated in a mouse model that it improves liver fibrosis, lipid accumulation, and inflammation caused by non-alcoholic steatohepatitis (NASH). This research result provides an option for the development of NASH therapeutics as well as a technology for creating growth factor and cytokine mimetic molecules with improved pharmacokinetics.
NASH is a liver disease in which fat accumulates in the liver, leading to inflammation and fibrosis. It can lead to serious complications such as cirrhosis and liver cancer. In recent years, the number of NASH patients is estimated to be 25-30% worldwide due to the increase in obesity and diabetes, and the development of new therapies is urgently needed.
Hepatocyte growth factor (HGF)*1 is known to play an important role in hepatocytes regeneration and protection by binding to the c-Met receptor.*1 However, it has the challenges of a short half-life in blood and limited administration methods, despite its potential as a therapeutic agent for NASH.
In this study, the research group developed an HGF mimetic molecule by newly identified cyclic peptides that bind to the c-Met receptor using in vitro mRNA display method*2 and grafting it into the crystallizable region (Fc) of an immunoglobulin. This HGF mimetic molecule overcomes the pharmacokinetic drawbacks of HGF by having the properties of Fc, which prolongs its half-life in blood circulation and allows for subcutaneous administration. When the HGF mimetic molecule was subcutaneously administered once a week to mice with NASH induced by a choline-deficient high-fat diet, liver fibrosis, inflammation, and fat accumulation were significantly improved compared to the control group.
This research result provides a new option for NASH therapeutics and provides a technical basis for creating growth factor and cytokine mimetic molecules that expand the range of therapeutic applications by improving pharmacokinetics.
Glossary
*1: Hepatocyte growth factor (HGF), c-Met receptor
Hepatocyte growth factor (HGF) is a protein that promotes cell growth, survival, and motility. The c-Met receptor is a receptor that specifically binds to HGF and transmits its signal into the cell. This signal transduction pathway is involved in various biological processes such as tissue repair, embryogenesis, and angiogenesis.
*2: In vitro mRNA display method
A method in which peptides and proteins are translated from a random mRNA library in a cell-free translation system, and selectively enriched and recovered by binding to the target. This selection is repeated to obtain peptides and proteins that bind strongly to the target.
Funder
This work was supported by the World Premier International Research Center Initiative (WPI), Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan, a Grant-in-Aid for JSPS Scientific Research (C) (20K06553) , a Grant-in-Aid for JSPS Challenging Research (21K18250) , and Program for Basic and Clinical Research on Hepatitis from the Japan Agency for Medical Research and Development (AMED) (JP21fk0210087), etc.
About the World Premier International Research Center Initiative (WPI)
The WPI program was launched in 2007 by Japan's Ministry of Education, Culture, Sports, Science and Technology (MEXT) to foster globally visible research centers boasting the highest standards and outstanding research environments. Numbering more than a dozen and operating at institutions throughout the country, these centers are given a high degree of autonomy, allowing them to engage in innovative modes of management and research. The program is administered by the Japan Society for the Promotion of Science (JSPS).
See the latest research news from the centers at the WPI News Portal: https://www.eurekalert.org/newsportal/WPI
Main WPI program site: www.jsps.go.jp/english/e-toplevel
Nano Life Science Institute (WPI-NanoLSI), Kanazawa University
Understanding nanoscale mechanisms of life phenomena by exploring “uncharted nano-realms”
Cells are the basic units of almost all life forms. We are developing nanoprobe technologies that allow direct imaging, analysis, and manipulation of the behavior and dynamics of important macromolecules in living organisms, such as proteins and nucleic acids, at the surface and interior of cells. We aim at acquiring a fundamental understanding of the various life phenomena at the nanoscale.
NanoLSI website: https://nanolsi.kanazawa-u.ac.jp/en/
Journal
iScience
Method of Research
Experimental study
Subject of Research
Animals
Article Title
A cyclic peptide-grafted Fc with hepatocyte growth factor functionality ameliorates hepatic fibrosis in a non-alcoholic steatohepatitis mouse model
Article Publication Date
2-Jul-2024