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.
Highlights
Hepatocyte growth factor (HGF) receptor, known as Met, is a member of the receptor tyrosine kinase family
The peptide library was constructed from a single mRNA library, the cyclic scaffold ensured that the D-library and the L-library covered different threedimensional spaces
As it is known that transactivation of Met can occur via epidermal growth factor (EGF)-dependent EGF receptor (EGFR) activation or through a constitutively activated EGFR pathway[20], we examined whether inhibition of EGF-induced phosphorylation of EGFR by the dimeric macrocycles caused the ‘bell-shaped’ response mentioned above
Summary
Hepatocyte growth factor (HGF) receptor, known as Met, is a member of the receptor tyrosine kinase family. 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 and strongly activate Met signalling pathways through receptor dimerization and induce various HGF-like cellular responses, such as branching morphogenesis, in human cells. Hepatocyte growth factor (HGF) receptor, known as Met or c-Met, is a class IV RTK that interacts with its specific ligand, HGF, through the Met ectodomain (extracellular domain) to form Met–HGF dimers[2,3,4] This event brings the respective intracellular tyrosine kinase domains into close proximity[5,6], promoting trans-phosphorylation (autophosphorylation) of tyrosine residues. Through the engineering of artificially selected macrocycles, we have developed agonists of a receptor-mediated signalling cascade, opening a unique opportunity to develop ‘non-protein’ regenerative medicines
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