PR73

**PR73** is a synthetic minihepcidin peptide that mimics the first 9 residues of hepcidin, designed as a highly potent inhibitor of ferroportin (Fpn), the sole iron exporter in mammals. It features modified unnatural amino acids, including a free cysteine at position 7 for disulfide bridge formation with Fpn Cys326, an aminohexanoic linker, and a palmitic amide tail that inserts into the membrane, enhancing binding affinity (KD ~37 nM) over native hepcidin through novel interactions like hydrogen bonding with Gln194. Structural studies by cryo-EM (PDB: 8DL7) reveal PR73 locks Fpn in an outward-facing conformation, inhibiting iron transport and inducing endocytosis/degradation, with preclinical efficacy in preventing iron overload models for conditions like β-thalassemia and hemochromatosis.[1][2][3]