Iron is an essential element for most life on Earth. In vertebrates, iron absorption, plasma iron levels, and tissue iron distribution are primarily regulated by the hepatic peptide hormone hepcidin. This functions by binding to and inducing the internalisation and subsequent lysosomal degradation of its receptor, ferroportin. Hepcidin, ferroportin and their regulators are, therefore, paramount in the upkeep of iron homeostasis and are promising targets for the diagnosis and treatment of iron-related conditions. This research concerns the development of peptide therapeutics based on two distinct methodologies.
The first focuses on HFE, the most frequently mutated protein in haemochromatosis, and the molecular function of which is still largely unclear. Briefly, peptide entities rationally designed to disrupt the interaction between HFE and transferrin receptor 1 (TfR1) will be explored with the intent of increasing hepcidin transcription. The results to date are encouraging with two of the peptides showing a significant decrease in HFE/TfR1 complex formation, relative to both untreated and unspecific peptide-treated cells, in an in situ proximity ligation assay (Duolink®).
The second approach entails hepcidin replacement. Mini-hepcidins are small hepcidin agonists amenable to optimisation of activity and drug-like properties, and thus are potentially applicable to the treatment or prevention of iron overload. In this strand, end-to-end cyclisation and N-methylation of mini-hepcidins is being examined for the introduction of favourable conformational restrictions and conferral of biostability, whilst retaining target affinity and specificity.
In the immediate future, the inhibitors for HFE/TfR1 complex formation will be examined for their capacity to modulate hepcidin transcription. In addition, the remaining analogues in the mini-hepcidin series will be synthesised and tested, not only for bioactivity, but also for stability and membrane permeability. NMR analysis will then be used to correlate the structure and conformational restrictions of the peptides with their physiological properties.