Macrocyclic peptide-based inhibition and imaging of hepatocyte growth factor.
Journal
Nature chemical biology
ISSN: 1552-4469
Titre abrégé: Nat Chem Biol
Pays: United States
ID NLM: 101231976
Informations de publication
Date de publication:
06 2019
06 2019
Historique:
received:
28
09
2018
accepted:
03
04
2019
entrez:
19
5
2019
pubmed:
19
5
2019
medline:
30
7
2019
Statut:
ppublish
Résumé
Activation of hepatocyte growth factor (HGF) by proteolytic processing is triggered in cancer microenvironments, and subsequent signaling through the MET receptor is involved in cancer progression. However, the structure of HGF remains elusive, and few small/medium-sized molecules can modulate HGF. Here, we identified HiP-8, a macrocyclic peptide consisting of 12 amino acids, which selectively recognizes active HGF. Biochemical analysis and real-time single-molecule imaging by high-speed atomic force microscopy demonstrated that HiP-8 restricted the dynamic domains of HGF into static closed conformations, resulting in allosteric inhibition. Positron emission tomography using HiP-8 as a radiotracer enabled noninvasive visualization and simultaneous inhibition of HGF-MET activation status in tumors in a mouse model. Our results illustrate the conformational change in proteolytic activation of HGF and its detection and inhibition by a macrocyclic peptide, which may be useful for diagnosis and treatment of cancers.
Identifiants
pubmed: 31101918
doi: 10.1038/s41589-019-0285-7
pii: 10.1038/s41589-019-0285-7
doi:
Substances chimiques
Macrocyclic Compounds
0
Peptides
0
Hepatocyte Growth Factor
67256-21-7
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Pagination
598-606Références
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