title: Artificial human Met agonists based on macrocycle scaffolds.
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.
authors.affiliation: Department of Chemistry, Graduate School of Science, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Ito
authors.affiliation: Division of Tumor Dynamics and Regulation, Cancer Research Institute, Kanazawa University, Kanazawa 920-1192, Japan.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Sakai
authors.affiliation: Division of Tumor Dynamics and Regulation, Cancer Research Institute, Kanazawa University, Kanazawa 920-1192, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: Department of Chemistry, Graduate School of Science, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Ozawa
authors.affiliation: National Institute of Advanced Industrial Science and Technology, Biological Information Research Center, Tokyo 135-0064, Japan.
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Hatta
authors.affiliation: National Institute of Advanced Industrial Science and Technology, Biological Information Research Center, Tokyo 135-0064, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Natsume
authors.affiliation: Division of Tumor Dynamics and Regulation, Cancer Research Institute, Kanazawa University, Kanazawa 920-1192, Japan.
authors.forename: Kunio
authors.initials: K
authors.lastname: Matsumoto
authors.affiliation: Department of Chemistry, Graduate School of Science, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Suga
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001665:Binding Sites; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019281:Dimerization; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D009024:Morphogenesis / Q000187:drug effects* / Q000235:genetics; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014945:Wound Healing / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D008024:Ligands; D010456:Peptides, Cyclic; D012333:RNA, Messenger; D017228:Hepatocyte Growth Factor; D019869:Phosphatidylinositol 3-Kinases; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases