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Artificial human Met agonists based on macrocycle scaffolds

Author

Listed:
  • Kenichiro Ito

    (Graduate School of Science, The University of Tokyo)

  • Katsuya Sakai

    (Cancer Research Institute, Kanazawa University)

  • Yoshinori Suzuki

    (Cancer Research Institute, Kanazawa University)

  • Naoya Ozawa

    (Graduate School of Science, The University of Tokyo)

  • Tomohisa Hatta

    (National Institute of Advanced Industrial Science and Technology, Biological Information Research Center)

  • Tohru Natsume

    (National Institute of Advanced Industrial Science and Technology, Biological Information Research Center)

  • Kunio Matsumoto

    (Cancer Research Institute, Kanazawa University)

  • Hiroaki Suga

    (Graduate School of Science, The University of Tokyo)

Abstract

Hepatocyte growth factor (HGF) receptor, also known as Met, is a member of the receptor tyrosine kinase family. The Met–HGF interaction regulates various signalling pathways involving downstream kinases, such as Akt and Erk. Met activation is implicated in wound healing of tissues via multiple biological responses triggered by the above-mentioned signalling cascade. Here we report the development of artificial Met-activating dimeric macrocycles. We identify Met-binding monomeric macrocyclic peptides by means of the RaPID (random non-standard peptide integrated discovery) system, and dimerize the respective monomers through rational design. These dimeric macrocycles specifically and strongly activate Met signalling pathways through receptor dimerization and induce various HGF-like cellular responses, such as branching morphogenesis, in human cells. This work suggests our approach for generating dimeric macrocycles as non-protein ligands for cell surface receptors can be useful for developing potential therapeutics with a broad range of potential applications.

Suggested Citation

  • Kenichiro Ito & Katsuya Sakai & Yoshinori Suzuki & Naoya Ozawa & Tomohisa Hatta & Tohru Natsume & Kunio Matsumoto & Hiroaki Suga, 2015. "Artificial human Met agonists based on macrocycle scaffolds," Nature Communications, Nature, vol. 6(1), pages 1-12, May.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7373
    DOI: 10.1038/ncomms7373
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