Cyclic Peptide-Based Biologics Regulating HGF-MET.
Using a random non-standard peptide integrated discovery system, we obtained cyclic peptides that bind to hepatocyte growth factor (HGF) or mesenchymal-epithelial transition factor. (MET) HGF-inhibitory peptide-8 (HiP-8) selectively bound to two-chain active HGF, but not to single-chain precursor HGF. HGF showed a dynamic change in its molecular shape in atomic force microscopy, but HiP-8 inhibited dynamic change in the molecular shape into a static status. The inhibition of the molecular dynamics of HGF by HiP-8 was associated with the loss of the ability to bind MET. HiP-8 could selectively detect active HGF in cancer tissues, and active HGF probed by HiP-8 showed co-localization with activated MET. Using HiP-8, cancer tissues with active HGF could be detected by positron emission tomography. HiP-8 seems to be applicable for the diagnosis and treatment of cancers. In contrast, based on the receptor dimerization as an essential process for activation, the cross-linking of the cyclic peptides that bind to the extracellular region of MET successfully generated an artificial ligand to MET. The synthetic MET agonists activated MET and exhibited biological activities which were indistinguishable from the effects of HGF. MET agonists composed of cyclic peptides can be manufactured by chemical synthesis but not recombinant protein expression, and thus are expected to be new biologics that are applicable to therapeutics and regenerative medicine.
['Sato|Hiroki|H|', 'Imamura|Ryu|R|', 'Suga|Hiroaki|H|', 'Matsumoto|Kunio|K|0000-0002-6532-4482', 'Sakai|Katsuya|K|']
D000818:Animals D001665:Binding Sites D001688:Biological Products D015972:Gene Expression Regulation, Neoplastic D017228:Hepatocyte Growth Factor D006801:Humans D009369:Neoplasms D010456:Peptides, Cyclic D011485:Protein Binding D019859:Proto-Oncogene Proteins c-met D015398:Signal Transduction
cyclic peptide HGF MET atomic force microscopy MET agonist PET imaging synthetic HGF