Total Synthesis of Human Hepcidin through Regioselective Disulfide-Bond Formation by using the Safety-Catch Cysteine Protecting Group 4,4′-Dimethylsulfinylbenzhydryl.

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 n M (non-native fold, 2), with 2 undergoing isomerization to 1 in the presence of ferroportin expressing cells. [ABSTRACT FROM AUTHOR]