Cyclic Peptide-Based Biologics Regulating HGF-MET

Abstract

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.

A novel agonist for the HGF receptor MET promotes differentiation of human pluripotent stem cells into hepatocyte‐like cells

“…The differentiation of mouse embryonic stem cells into HLCs with HGF, dexamethasone, and HGF + dexamethasone at their progenitor stage (step 3 in our present protocol) clearly enhanced hepatic maturation (Shiraki et al, 2008). Furthermore, K1K1 is a ligand mediating phosphorylation of MET (via p-Akt and p-ERK) as we demonstrated previously (de Nola et al, 2022) and consistent with another report (Sato et al, 2020). We also confirmed MET was activated in the present study.…”

Dimerization of kringle 1 domain from hepatocyte growth factor/scatter factor provides a potent MET receptor agonist

“…Several molecules have been developed in recent years to overcome the limitations of HGF/SF in therapy. These included engineered variants of the natural growth factor ( Cassano et al, 2008 ; Sinha Roy et al, 2010 ), agonistic monoclonal antibodies ( Gallo et al, 2014 ; Kim et al, 2019 ), synthetic cyclic peptides ( Sato et al, 2020 ), and aptamers ( Ueki et al, 2020 ). All the engineered variants of HGF/SF developed thus far, however, contain the high-affinity HSPG-binding site present in the N-domain and thus share with HGF/SF the feature of limited diffusion and tissue penetration.…”

Dimerization of kringle 1 domain from hepatocyte growth factor/scatter factor provides a potent minimal MET receptor agonist

“…Several MET agonists have been developed over the years, most notably Magic-F1 (56), eNK1 (57), agonistic monoclonal antibodies (58, 59), a group of synthetic cyclic peptides (60) and recently an aptamer (61). Most relevant to our study are Magic-F1 and eNK1 as they are both based on dimers of HGF/SF domains.…”