PT  - JOURNAL ARTICLE
AU  - Giovanni de Nola
AU  - Bérénice Leclercq
AU  - Alexandra Mougel
AU  - Solenne Taront
AU  - Claire Simonneau
AU  - Federico Forneris
AU  - Eric Adriaenssens
AU  - Hervé Drobecq
AU  - Luisa Iamele
AU  - Laurent Dubuquoy
AU  - Oleg Melnyk
AU  - Ermanno Gherardi
AU  - Hugo de Jonge
AU  - Jérôme Vicogne
TI  - Dimerization of kringle 1 domain from hepatocyte growth factor/scatter factor provides a potent minimal MET receptor agonist
AID  - 10.1101/2020.07.20.212654
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2020.07.20.212654
4099  - http://biorxiv.org/content/early/2022/02/19/2020.07.20.212654.short
4100  - http://biorxiv.org/content/early/2022/02/19/2020.07.20.212654.full
AB  - Hepatocyte Growth Factor/Scatter Factor (HGF/SF) and its cognate receptor MET play several essential roles in embryogenesis and regeneration in post-natal life of epithelial organs such as liver, kidney, lung, and pancreas, prompting a strong interest in harnessing HGF/SF-MET signalling for regeneration of epithelial organs after acute or chronic damage. The limited stability and tissue diffusion of native HGF/SF, however, which reflect the tightly controlled, local mechanism of action of the morphogen, have led to a major search for HGF/SF mimics for therapy. In this work, we describe the rational design, production and characterisation of K1K1, a novel minimal MET agonist consisting of two copies of the kringle 1 domain of HGF/SF placed in tandem. K1K1 is highly stable and displays biological activities equivalent or superior to native HGF/SF in a variety of in vitro assay systems and in a mouse model of liver disease. These data suggest that this engineered ligand may find wide applications in acute and chronic diseases of the liver and other epithelial organs dependent on MET activation.Competing Interest StatementThe authors declare no competing interests at date of submission but the Universities of Lille and Pavia have filed a joint patent on K1K1 (patent number WO2016116578A1).