Artificial human Met agonists based on macrocycle scaffolds

• DOI: 10.1038/ncomms7373
• Publication Date: 2015-03-11T12:04:31Z
• Authors: Kenichiro Ito; Katsuya Sakai; Yoshinori Suzuki; Naoya Ozawa; Tomohisa Hatta; Tohru Natsume; Kunio Matsumoto; Hiroaki Suga
• Keywords: Receptor Protein-Tyrosine Kinases

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 Akt and Erk. Met activation implicated in wound healing tissues via multiple biological responses triggered by above-mentioned cascade. Here we report development artificial Met-activating dimeric macrocycles. We identify Met-binding monomeric macrocyclic peptides means RaPID (random non-standard peptide integrated discovery) system, dimerize respective monomers through rational design. These macrocycles specifically strongly activate dimerization induce HGF-like cellular responses, branching morphogenesis, human cells. This work suggests our approach for generating non-protein ligands cell surface receptors can be useful developing potential therapeutics with broad range applications.