Cargando…

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

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 fir...

Descripción completa

Detalles Bibliográficos
Autores principales: Simonneau, Claire, Bérénice Leclercq, Mougel, Alexandra, Adriaenssens, Eric, Paquet, Charlotte, Raibaut, Laurent, Ollivier, Nathalie, Drobecq, Hervé, Marcoux, Julien, Cianférani, Sarah, Tulasne, David, de Jonge, Hugo, Melnyk, Oleg, Vicogne, Jérôme
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Royal Society of Chemistry 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5496502/
https://www.ncbi.nlm.nih.gov/pubmed/28717459
http://dx.doi.org/10.1039/c4sc03856h
_version_ 1783247992840519680
author Simonneau, Claire
Bérénice Leclercq,
Mougel, Alexandra
Adriaenssens, Eric
Paquet, Charlotte
Raibaut, Laurent
Ollivier, Nathalie
Drobecq, Hervé
Marcoux, Julien
Cianférani, Sarah
Tulasne, David
de Jonge, Hugo
Melnyk, Oleg
Vicogne, Jérôme
author_facet Simonneau, Claire
Bérénice Leclercq,
Mougel, Alexandra
Adriaenssens, Eric
Paquet, Charlotte
Raibaut, Laurent
Ollivier, Nathalie
Drobecq, Hervé
Marcoux, Julien
Cianférani, Sarah
Tulasne, David
de Jonge, Hugo
Melnyk, Oleg
Vicogne, Jérôme
author_sort Simonneau, Claire
collection PubMed
description 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.
format Online
Article
Text
id pubmed-5496502
institution National Center for Biotechnology Information
language English
publishDate 2015
publisher Royal Society of Chemistry
record_format MEDLINE/PubMed
spelling pubmed-54965022017-07-17 Semi-synthesis of a HGF/SF kringle one (K1) domain scaffold generates a potent in vivo MET receptor agonist Simonneau, Claire Bérénice Leclercq, Mougel, Alexandra Adriaenssens, Eric Paquet, Charlotte Raibaut, Laurent Ollivier, Nathalie Drobecq, Hervé Marcoux, Julien Cianférani, Sarah Tulasne, David de Jonge, Hugo Melnyk, Oleg Vicogne, Jérôme Chem Sci Chemistry 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. Royal Society of Chemistry 2015-03-01 2015-01-29 /pmc/articles/PMC5496502/ /pubmed/28717459 http://dx.doi.org/10.1039/c4sc03856h Text en This journal is © The Royal Society of Chemistry 2015 http://creativecommons.org/licenses/by-nc/3.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 Unported License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Chemistry
Simonneau, Claire
Bérénice Leclercq,
Mougel, Alexandra
Adriaenssens, Eric
Paquet, Charlotte
Raibaut, Laurent
Ollivier, Nathalie
Drobecq, Hervé
Marcoux, Julien
Cianférani, Sarah
Tulasne, David
de Jonge, Hugo
Melnyk, Oleg
Vicogne, Jérôme
Semi-synthesis of a HGF/SF kringle one (K1) domain scaffold generates a potent in vivo MET receptor agonist
title Semi-synthesis of a HGF/SF kringle one (K1) domain scaffold generates a potent in vivo MET receptor agonist
title_full Semi-synthesis of a HGF/SF kringle one (K1) domain scaffold generates a potent in vivo MET receptor agonist
title_fullStr Semi-synthesis of a HGF/SF kringle one (K1) domain scaffold generates a potent in vivo MET receptor agonist
title_full_unstemmed Semi-synthesis of a HGF/SF kringle one (K1) domain scaffold generates a potent in vivo MET receptor agonist
title_short Semi-synthesis of a HGF/SF kringle one (K1) domain scaffold generates a potent in vivo MET receptor agonist
title_sort semi-synthesis of a hgf/sf kringle one (k1) domain scaffold generates a potent in vivo met receptor agonist
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5496502/
https://www.ncbi.nlm.nih.gov/pubmed/28717459
http://dx.doi.org/10.1039/c4sc03856h
work_keys_str_mv AT simonneauclaire semisynthesisofahgfsfkringleonek1domainscaffoldgeneratesapotentinvivometreceptoragonist
AT bereniceleclercq semisynthesisofahgfsfkringleonek1domainscaffoldgeneratesapotentinvivometreceptoragonist
AT mougelalexandra semisynthesisofahgfsfkringleonek1domainscaffoldgeneratesapotentinvivometreceptoragonist
AT adriaenssenseric semisynthesisofahgfsfkringleonek1domainscaffoldgeneratesapotentinvivometreceptoragonist
AT paquetcharlotte semisynthesisofahgfsfkringleonek1domainscaffoldgeneratesapotentinvivometreceptoragonist
AT raibautlaurent semisynthesisofahgfsfkringleonek1domainscaffoldgeneratesapotentinvivometreceptoragonist
AT olliviernathalie semisynthesisofahgfsfkringleonek1domainscaffoldgeneratesapotentinvivometreceptoragonist
AT drobecqherve semisynthesisofahgfsfkringleonek1domainscaffoldgeneratesapotentinvivometreceptoragonist
AT marcouxjulien semisynthesisofahgfsfkringleonek1domainscaffoldgeneratesapotentinvivometreceptoragonist
AT cianferanisarah semisynthesisofahgfsfkringleonek1domainscaffoldgeneratesapotentinvivometreceptoragonist
AT tulasnedavid semisynthesisofahgfsfkringleonek1domainscaffoldgeneratesapotentinvivometreceptoragonist
AT dejongehugo semisynthesisofahgfsfkringleonek1domainscaffoldgeneratesapotentinvivometreceptoragonist
AT melnykoleg semisynthesisofahgfsfkringleonek1domainscaffoldgeneratesapotentinvivometreceptoragonist
AT vicognejerome semisynthesisofahgfsfkringleonek1domainscaffoldgeneratesapotentinvivometreceptoragonist