期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 25, 期 4, 页码 763-766出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2014.12.094
关键词
Minihepcidins; Peptides; S-alkylation of peptides; Iron
资金
- NIH [R01 DK090554]
- Dean's Office of the David Geffen School of Medicine at UCLA
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. (C) 2015 Elsevier Ltd. All rights reserved.
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