Thiol-derivatized minihepcidins retain biological activity

Abstract

Minihepcidins are small peptides that mimic biological activity of the iron-regulatory hormone hepcidin. Structurally, they contain thiol-free-cysteine residue in position 7 which is crucial for their bioactivity. Nonetheless, free sulfhydryl group is not desirable in pharmaceutical entities as it may lead to dermatological side effects. Moreover free thiol moiety is quite reactive and depending on conditions/reagents may be alkylated and/or oxidized giving various Cys-derivatives: S-alkyl cysteines, sulfoxides, sulfones, disulfides, cysteinesulfinic and cysteic acids. To limit such reactivity and maintain bioactivity of minihepcidin(s) we used thiol-protection strategy based on activated vinyl thioethers. Novel S-protected analogs of physiologically active minihepcidin PR73 were synthesized and tested in vitro showing activity comparable to parental molecule. The most active compound, PR73SH was also tested in vivo showing activity profile analogous to PR73. Collectively, our findings suggest that S-vinyl-derivatization of minihepcidin(s) may be a suitable approach in the development of physiologically active agonists of hepcidin.

Structure-function analysis of ferroportin defines the binding site and an alternative mechanism of action of hepcidin

“…The profound block of iron export through K8R was achieved despite impaired Fpn degradation, as determined by western blotting ( Figure 5B), and despite the lack of degradation or punctate structures characteristic of endocytosis, as shown by microscopy ( Figure 5C). PR73, 41 a minihepcidin that was engineered to bind to Fpn more strongly than hepcidin, was 10 times more potent than hepcidin in inducing ferritin retention without endocytic degradation of K8R Fpn (supplemental Figure 12).…”

Hepcidin and its therapeutic potential in neurodegenerative disorders

“…They discovered specific hydrophobic/aromatic residues required for hepcidin‐Fpn1 binding and obtained evidence in vitro that a thiol‐disulfide interaction between Fpn1 C326 and the hepcidin disulfide cage may stabilize binding . They showed that S‐vinyl‐derivatization of minihepcidin(s) may be a suitable approach in the development of physiologically active agonists of hepcidin . They also improved the half‐life and potency of these peptides through engineering and demonstrated that treatment with minihepcidins to mice mimics the iron‐restrictive effect of endogenous hepcidin, as reflected by improved anemia, iron overload, ineffective erythropoiesis, the lifespan of circulating red blood cells and splenomegaly, and reduced hemichrome formation and ROS .…”

Anaemia in chronic kidney disease- new treatment options

“…Other hepcidin sequestering agents to be considered as a novel treatment options include mimicking soluble hemojuvelin; suppression of bone morphogenic protein (BMP) receptors as dorsomorphin; disruption IL-6 activation and there the action of tocilizumab, neutralizing antibody to IL-6, that has been already approved for rheumatoid arthritis and has been proved to ameliorate anaemia in Castleman's disease; and the inhibition of a transcription factor signal transducer and activator of transcription 3 (STAT3 inhibitor). Antisense oligonucleotides (ASOs) and RNA interference (RNAi) are the other therapeutic strategies for targeting transcription and translation of hepcidin [24] and minihepcidins (small active peptides)mimetics of iron-regulatory hormone hepcidin [25].…”