Journal Article

Artificial human Met agonists based on macrocycle scaffolds

Sakai, Katsuya, Suzuki, Yoshinori, Suga, Hiroaki, Ito, Kenichiro, Matsumoto, Kunio, Ozawa, Naoya, Hatta, Tomohisa, Natsume, Tohru

2015

Overview

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. Activation of the Met receptor by hepatocyte growth factor requires Met receptor dimerization. Here, the authors identify Met-binding peptide macrocycles that, in a dimeric form as a result of chemical crosslinking, induce Met receptor dimerization and activation in cultured human cells.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Pub. Group
• Subject: 13 / 13/95 / 631/80/86 / 631/92/612/1234 / 96 / 96/47 / 96/95 / Antineoplastic Agents - chemical synthesis / Antineoplastic Agents - pharmacology / 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 / Hepatocyte Growth Factor - metabolism / Humanities and Social Sciences / Humans / Ligands / Morphogenesis - drug effects / Morphogenesis - genetics / multidisciplinary / Peptides / Peptides, Cyclic - chemical synthesis / Peptides, Cyclic - pharmacology / 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 - agonists / Proto-Oncogene Proteins c-met - genetics / Proto-Oncogene Proteins c-met - metabolism / RNA, Messenger - genetics / RNA, Messenger - metabolism / Science / Science (multidisciplinary) / Signal Transduction / Wound Healing - drug effects