title: Total synthesis of human hepcidin through regioselective disulfide-bond formation by using the safety-catch cysteine protecting group 4,4'-dimethylsulfinylbenzhydryl.
abstract: A safety-catch cysteine protecting group, S-4,4'-dimethylsulfinylbenzhydryl (Msbh), was designed and developed to expand the capabilities of synthetic strategies for the regioselective formation of disulfide bonds in cysteine-rich peptides. The directed regioselective synthesis of human hepcidin, which contains four disulfide bonds, was undertaken and led to a high-resolution NMR structure under more physiologically relevant conditions than previously. Conversely, hepcidin synthesized with the formerly assigned vicinal disulfide-bond connectivity displayed significant conformational heterogeneity under similar conditions. The two synthetic forms of human hepcidin induced ferroportin internalization with apparent EC50 values of 2.0 (native fold, 1) and 4.4 nM (non-native fold, 2), with 2 undergoing isomerization to 1 in the presence of ferroportin expressing cells.
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland, 4072 (Australia).
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Dekan
authors.forename: Mehdi
authors.initials: M
authors.lastname: Mobli
authors.forename: Michael W
authors.initials: MW
authors.lastname: Pennington
authors.forename: Eileen
authors.initials: E
authors.lastname: Fung
authors.forename: Elizabeta
authors.initials: E
authors.lastname: Nemeth
authors.forename: Paul F
authors.initials: PF
authors.lastname: Alewood
mesh_terms: D000595:Amino Acid Sequence; D001559:Benzhydryl Compounds / Q000737:chemistry*; D003545:Cysteine / Q000737:chemistry*; D004220:Disulfides / Q000737:chemistry*; D064451:Hepcidins / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D008969:Molecular Sequence Data; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013237:Stereoisomerism
chemical_list: D001559:Benzhydryl Compounds; D004220:Disulfides; D064451:Hepcidins; D003545:Cysteine
keywords: disulfide bonds; hepcidin; peptides; protecting groups; regioselective folding