1. Artificial human Met agonists based on macrocycle scaffolds.
- Author
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Ito K, Sakai K, Suzuki Y, Ozawa N, Hatta T, Natsume T, Matsumoto K, and Suga H
- Subjects
- Antineoplastic Agents chemical synthesis, Binding Sites, Cell Line, Tumor, Cell Survival drug effects, Dimerization, Epithelial Cells drug effects, Epithelial Cells metabolism, Epithelial Cells pathology, Extracellular Signal-Regulated MAP Kinases genetics, Extracellular Signal-Regulated MAP Kinases metabolism, Gene Expression Regulation, Hepatocyte Growth Factor genetics, Humans, Ligands, Morphogenesis genetics, Peptides, Cyclic chemical synthesis, Phosphatidylinositol 3-Kinases genetics, Phosphatidylinositol 3-Kinases metabolism, Phosphorylation, Protein Binding, Proto-Oncogene Proteins c-akt genetics, Proto-Oncogene Proteins c-akt metabolism, Proto-Oncogene Proteins c-met genetics, Proto-Oncogene Proteins c-met metabolism, RNA, Messenger genetics, RNA, Messenger metabolism, Signal Transduction, Wound Healing drug effects, Antineoplastic Agents pharmacology, Hepatocyte Growth Factor metabolism, Morphogenesis drug effects, Peptides, Cyclic pharmacology, Proto-Oncogene Proteins c-met agonists
- 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.
- Published
- 2015
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