A minimal hepatocyte growth factor mimic acting as a powerful agonist of the MET receptor tyrosine kinase for regeneration of epithelial tissues and organs

Abstract

AbstractDegenerative diseases of major internal epithelial organs such as liver, lung, and kidney account for more than one third of mortality worldwide. The huge demand for drugs able to limit epithelial tissue degradation and eventually restore its functionality, place mimics of the hepatocyte growth factor/scatter factor (HGF/SF), the physiological ligand for the MET receptor tyrosine kinase, at the forefront of potential drug candidates. HGF/SF is a growth and motility factor with essential physiological roles in development and regeneration of epithelial organs. Unfortunately, HGF/SF itself is unsuitable for therapy because naturally the factor acts only locally as a pleiotropic factor and has a poor in vivo distribution and shelf-life profile. We have therefore designed, produced, solved the crystal structure, and characterized the biochemical and biological properties of K1K1, a new engineered fragment of HGF/SF optimised for applications in tissue/organ regeneration. K1K1, a covalent dimer of the first kringle domain of HGF/SF, is recombinantly produced in bacterial cells, shows superior stability at physiological pH and ionic strength and is a potent receptor agonist as demonstrated in a wide range of biological assays with cells in culture and several in vivo studies. K1K1 has broad potential in regenerative medicine with diseases such as acute liver failure, non-alcoholic steatohepatitis, chronic obstructive pulmonary disease, acute kidney injury, and currently lung injury related to respiratory viral infection due to COVID-19.SignificanceThe role of HGF/SF and the MET signalling pathway in homeostasis, protection, and regeneration of major organs such as liver, lung, and kidney has been well established. The increasing health burden due to degenerative diseases in our expanding and aging global population has driven research in regenerative therapies and while cell-based therapies have shown promising results, huge costs and technological challenges will hinder widespread application for the foreseeable future. Instead, protein-based therapy, in which a potent MET receptor agonist is administered to patients seems a viable alternative in many diseases currently lacking effective treatment. We describe here the design and characterisation of K1K1, a potent minimal Met receptor agonist with superior properties and equipotent biological activities when compared to native HGF/SF.