title: 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.
authors.affiliation: Department of Medicine, University of California at Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA.
authors.forename: Eileen
authors.initials: E
authors.lastname: Fung
authors.affiliation: Department of Medicine, University of California at Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA.
authors.forename: Kristine
authors.initials: K
authors.lastname: Chua
authors.affiliation: Department of Medicine, University of California at Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA.
authors.forename: Tomas
authors.initials: T
authors.lastname: Ganz
authors.affiliation: Department of Medicine, University of California at Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA.
authors.forename: Elizabeta
authors.initials: E
authors.lastname: Nemeth
authors.affiliation: Department of Medicine, University of California at Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA; Department of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles, 760 Westwood Plaza, Los Angeles, CA 90095, USA. Electronic address: pruchala@mednet.ucla.edu.
authors.forename: Piotr
authors.initials: P
authors.lastname: Ruchala
mesh_terms: D040761:Biomimetic Materials / Q000737:chemistry / Q000494:pharmacology; D064451:Hepcidins / Q000737:chemistry* / Q000494:pharmacology*; D007501:Iron / Q000737:chemistry; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D064451:Hepcidins; D010455:Peptides; D013438:Sulfhydryl Compounds; D007501:Iron
keywords: Iron; Minihepcidins; Peptides; S-alkylation of peptides