Issue 3, 2015

Semi-synthesis of a HGF/SF kringle one (K1) domain scaffold generates a potent in vivo MET receptor agonist

Abstract

The development of MET receptor agonists is an important goal in regenerative medicine, but is limited by the complexity and incomplete understanding of its interaction with HGF/SF (Hepatocyte Growth Factor/Scatter Factor). NK1 is a natural occurring agonist comprising the N-terminal (N) and the first kringle (K1) domains of HGF/SF. In the presence of heparin, NK1 can self-associate into a “head to tail” dimer which is considered as the minimal structural module able to trigger MET dimerization and activation whereas isolated K1 and N domains showed a weak or a complete lack of agonistic activity respectively. Starting from these structural and biological observations, we investigated whether it was possible to recapitulate the biological properties of NK1 using a new molecular architecture of isolated N or K1 domains. Therefore, we engineered multivalent N or K1 scaffolds by combining synthetic and homogeneous site-specifically biotinylated N and K1 domains (NB and K1B) and streptavidin (S). NB alone or in complex failed to activate MET signaling and to trigger cellular phenotypes. Importantly and to the contrary of K1B alone, the semi-synthetic K1B/S complex mimicked NK1 MET agonist activity in cell scattering, morphogenesis and survival phenotypic assays. Impressively, K1B/S complex stimulated in vivo angiogenesis and, when injected in mice, protected the liver against fulminant hepatitis in a MET dependent manner whereas NK1 and HGF were substantially less potent. These data reveal that without N domain, proper multimerization of K1 domain is a promising strategy for the rational design of powerful MET agonists.

Graphical abstract: Semi-synthesis of a HGF/SF kringle one (K1) domain scaffold generates a potent in vivo MET receptor agonist

Supplementary files

Article information

Article type
Edge Article
Submitted
12 Dec 2014
Accepted
19 Jan 2015
First published
29 Jan 2015
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2015,6, 2110-2121

Semi-synthesis of a HGF/SF kringle one (K1) domain scaffold generates a potent in vivo MET receptor agonist

C. Simonneau, Bérénice Leclercq, A. Mougel, E. Adriaenssens, C. Paquet, L. Raibaut, N. Ollivier, H. Drobecq, J. Marcoux, S. Cianférani, D. Tulasne, H. de Jonge, O. Melnyk and J. Vicogne, Chem. Sci., 2015, 6, 2110 DOI: 10.1039/C4SC03856H

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