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Constructing Cyclic Peptides Using an On-Tether Sulfonium Center
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Artificial human Met agonists based on macrocycle scaffolds.

Kenichiro Ito1, Katsuya Sakai2, Yoshinori Suzuki2

  • 1Department of Chemistry, Graduate School of Science, The University of Tokyo, Tokyo 113-0033, Japan.

Nature Communications
|March 12, 2015
PubMed
Summary

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Researchers developed artificial dimeric macrocycles that activate the Met receptor tyrosine kinase. These novel compounds mimic hepatocyte growth factor (HGF) effects, promoting cell responses like branching morphogenesis for potential therapeutic applications.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Drug Discovery

Background:

  • Hepatocyte growth factor (HGF) receptor (Met) is a receptor tyrosine kinase crucial for tissue repair.
  • Met signaling pathways, including Akt and Erk, regulate biological responses.
  • Met activation is vital for wound healing and other cellular processes.

Purpose of the Study:

  • To develop artificial dimeric macrocycles that activate Met.
  • To create non-protein ligands for cell surface receptors.
  • To explore potential therapeutic applications of Met-activating compounds.

Main Methods:

  • Utilized the RaPID system to identify Met-binding monomeric macrocyclic peptides.
  • Employed rational design to dimerize monomeric peptides.

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  • Assessed Met signaling pathway activation and cellular responses in human cells.

    • Main Results:

    • Successfully developed dimeric macrocycles that specifically and strongly activate Met signaling.
    • Demonstrated that these macrocycles induce HGF-like cellular responses, including branching morphogenesis.
    • Confirmed activation occurs through Met receptor dimerization.

    Conclusions:

    • Artificial dimeric macrocycles can effectively activate Met signaling pathways.
    • This approach offers a novel method for generating non-protein ligands for cell surface receptors.
    • The developed macrocycles hold promise for developing therapeutics with diverse applications.