The disulfide bond plays an important role in biological systems. It defines global conformation, and ultimately the biological activity and stability of the peptide or protein. It is frequently present, singly or multiply, in biologically important peptide hormones and toxins. Numerous disulfide-containing peptides have been approved by the regulatory agencies as marketed drugs. Chemical synthesis is one of the prerequisite tools needed to gain deep insights into the structure-function relationships of these biomolecules. Along with the development of solid-phase peptide synthesis, a number of methods of disulfide construction have been established. This minireview will focus on the regiospecific, stepwise construction of multiple disulfides used in the chemical synthesis of peptides. We intend for this article to serve a reference for peptide chemists conducting complex peptide syntheses and also hope to stimulate the future development of disulfide methodologies.
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