HGF

HGF (hepatocyte growth factor) is the only known ligand of the c-Met (MET) receptor and one of the key tools for researchers working on tissue regeneration, anti-fibrosis and cell-proliferation signalling. Chemically it is not a peptide or a peptide analogue at all, but a large two-chain glycoprotein of about 90 kDa: an α- and a β-chain joined by a disulfide bridge, formed from an inactive single-chain precursor (pro-HGF) by proteolytic cleavage.

Structurally HGF is about one third identical to plasminogen and carries four kringle domains and a serine-protease-like domain. However, that protease domain is catalytically inactive: it has lost the residues of the catalytic triad. HGF is, in essence, a protease scaffold that evolution has repurposed into a growth factor.

That link to c-Met is exactly what makes HGF difficult: activation of c-Met launches an "invasive growth" programme (proliferation, cell scattering, morphogenesis, angiogenesis), and the same axis is a target for oncology drugs that inhibit it.

Mice lacking HGF or Met die in utero with defects of the placenta, liver and migration of muscle precursors. This is not a subtle modifier but an essential developmental gene.

Development status, honestly. There is no approved HGF agonist anywhere in the world. The recombinant protein is almost unusable as a systemic drug: a very short plasma half-life, strong binding to heparan sulfates, rapid hepatic clearance, and complex, expensive manufacture of a glycosylated two-chain protein. So clinical development took two roundabout routes: gene therapy with a plasmid encoding HGF (VM202/Engensis; phase 2 positive, phase 3 in diabetic neuropathy did not meet the primary endpoint), and local delivery of the recombinant protein (intrathecal KP-100IT in acute spinal cord injury).

A detailed analysis of the mechanism, the evidence base and the limitations is in the HGF monograph. Related catalogue directions: healing and regeneration, in particular B7-33 (an antifibrotic relaxin analogue on a different receptor axis, RXFP1) and ARA-290 (neuroregeneration).