Abstract

The peptide hormone hepcidin is one of the key regulators of iron absorption, plasma iron levels, and tissue iron distribution. Hepcidin functions by binding to and inducing the internalisation and subsequent lysosomal degradation of ferroportin, which reduces both iron absorption in the gut and export of iron from storage to ultimately decrease systemic iron levels. The key interaction motif in hepcidin has been localised to the highly conserved N-terminal region, comprising the first nine amino acid residues, and has led to the development of mini-hepcidin analogs that induce ferroportin internalisation and have improved drug-like properties. In this work, we have investigated the use of head-to-tail cyclisation and N-methylation of mini-hepcidin as a strategy to increase oral bioavailability by reducing proteolytic degradation and enhancing membrane permeability. We found that backbone cyclisation and N-methylation was well-tolerated in the mini-hepcidin analogues, with the macrocylic analogues often surpassing their linear counterparts in potency. Both macrocyclisation and backbone N-methylation were found to improve the stability of the mini-hepcidins, however, there was no effect on membrane-permeabilizing activity.

Highlights

  • Mass spectrometry (MS) was performed using an ABSciex API 2000TM coupled to an Agilent 1260 Infinity, and analytical liquid chromatography mass spectroscopy (LCMS) was performed using the same system equipped with a Kinetex® 2.6 μm C18 100 Å, 50 × 2.1 mm LC column

  • In the design of our first generation of mini-hepcidin analogues, we investigated if single modifications to the sequence could be introduced without affecting biological activity

  • We synthesised a set of peptides containing a single N-methylation at each residue and a head-to-tail backbone cyclic analogue

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Summary

Introduction

The highly conserved hepatocyte-secreted peptide hormone hepcidin is the primary regulator of iron absorption, plasma iron levels, and tissue iron distribution [1]. Hepcidin functions by binding to and either occluding or inducing the internalisation and lysosomal degradation of its receptor, ferroportin (FPN) [2,3]. This reduces both iron absorption in the gut and export of iron from storage organs, lowering systemic iron levels. Hepcidin has been found to be produced locally and perform important functions with physiological and pathological implications for organ homeostasis [4,5,6]

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