Total Synthesis of Human Hepcidin through Regioselective Disulfide‐Bond Formation by using the Safety‐Catch Cysteine Protecting Group 4,4′‐Dimethylsulfinylbenzhydryl |
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| Authors: | Zoltan Dekan Dr. Mehdi Mobli Dr. Michael W. Pennington Dr. Eileen Fung Dr. Elizabeta Nemeth Prof. Paul F. Alewood |
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| Affiliation: | 1. Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland, 4072 (Australia);2. Centre for Advanced Imaging, The University of Queensland, St Lucia, Queensland, 4072 (Australia);3. Peptides International, Inc, Louisville, KY 40299 (USA);4. David Geffen School of Medicine, University of California, Los Angeles, CA 90095 (USA) |
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| 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. |
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| Keywords: | disulfide bonds hepcidin peptides protecting groups regioselective folding |
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