Growth hormone (GH) is a potent anabolic hormone; deficiency results in extreme short stature and excess in gigantism and acromegaly. It is just over 50 years since Raben first demonstrated the dramatic impact of GH replacement on linear growth in a young boy with pituitary infantilism. Since then milestones in GH research have included identification of the GH binding protein (1986), the crystal structure of GH (1987), cloning of the GH receptor (1987) and the discovery of a GH antagonist (1990). Studies in patients with GH insensitivity, secondary to mutations in the GH receptor, have allowed the elucidation of the molecular interaction of GH with its receptor and the mechanism underlying activation of GH receptor signalling. Based on this understanding of the structure and physiology of GH we have been investigating the rational design of novel GH agonists and antagonists. We have examined tandem fusions of GH with flexible, rigid, and glycosylated linkers, addition of lipid anchors to both GH and its binding protein and the generation of ligand-receptor fusions through flexible peptide linkers. Despite apparent rational design, tests of bioactivity often produce surprising and unexpected results with the addition of a lipid anchor to GH creating an antagonist and a GH ligand-receptor fusion a potent agonist. Ligand-receptor fusions have unique properties forming a partially inactive complex in solution, with delayed clearance, whilst providing a constant supply of active GH that promotes growth. These novel GH constructs generate long-acting GH therapies with the potential for monthly dosing which would be a major advance over current daily treatment regimens.
Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding: No specific grant from any funding agency in the public, commercial or not-for-profit sector.
Generously supported by the Clinical Endocrinology Trust.