Particularly in the field of middle- and top-down peptide and protein analysis, 
disulfide bridges can severely hinder fragmentation and thus impede sequence 
analysis (coverage). Here we present an on-line/electrochemistry/ESI-FTICR-MS 
approach, which was applied to the analysis of the primary structure of 
oxytocin, containing one disulfide bridge, and of hepcidin, containing four 
disulfide bridges. The presented workflow provided up to 80% (on-line) 
conversion of disulfide bonds in both peptides. With minimal sample preparation, 
such reduction resulted in a higher number of peptide backbone cleavages upon 
CID or ETD fragmentation, and thus yielded improved sequence coverage. The cycle 
times, including electrode recovery, were rapid and, therefore, might very well 
be coupled with liquid chromatography for protein or peptide separation, which 
has great potential for high-throughput analysis.