Ito Kenichiro, Sakai Katsuya, Suzuki Yoshinori, Ozawa Naoya, Hatta Tomohisa, Natsume Tohru, Matsumoto Kunio, Suga Hiroaki
Department of Chemistry, Graduate School of Science, The University of Tokyo, Tokyo 113-0033, Japan.
Division of Tumor Dynamics and Regulation, Cancer Research Institute, Kanazawa University, Kanazawa 920-1192, Japan.
Nat Commun. 2015 Mar 11;6:6373. doi: 10.1038/ncomms7373.
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.
肝细胞生长因子（HGF）受体，也称为Met，是受体酪氨酸激酶家族的成员。Met-HGF相互作用调节涉及下游激酶（如Akt和Erk）的各种信号通路。Met激活通过上述信号级联引发的多种生物学反应参与组织的伤口愈合。在此，我们报告了人工Met激活二聚大环化合物的开发。我们通过RaPID（随机非标准肽整合发现）系统鉴定Met结合单体大环肽，并通过合理设计使各自的单体二聚化。这些二聚大环化合物通过受体二聚化特异性且强烈地激活Met信号通路，并在人类细胞中诱导各种HGF样细胞反应，如分支形态发生。这项工作表明，我们生成作为细胞表面受体非蛋白质配体的二聚大环化合物的方法，对于开发具有广泛潜在应用的潜在治疗药物可能是有用的。
