ABSTRACT
Disulfide bridges are key structural features of many peptides and proteins, with a fundamental role in the folding and stabilization of their bioactive conformations [1-3]. The unique reactivity of cysteine and the selectivity requirements inherent in correct cystine pairing combine to make disulfidecontaining peptides demanding synthetic targets. Interest in disulfide formation has not been limited to the reproduction of the patterns of natural structures; rather, it has often extended to the engineering of artificial disulfide bonds into natural or de novo-designed peptide molecules for different purposes: conformational restriction, mimetization of active sites, immunoconjugation, etc. The substantial literature in this field has been reviewed in depth in several publications [4-9]. The variety of methods described to form intramolecular (cyclic) and intermolecular (homo-and heteromeric) disulfides can be conveniently grouped into three main approaches [5]: (1) disulfides formed by oxidation of free thiol precursors, (2) disulfides formed from symmetrically S-protected precursors, and (3) directed disulfide formation from unsymmetrically protected precursors. The first two approaches are applicable to monomeric peptides with single or multiple disulfides, as well as parallel bis-cystine homodimers. Approach (3) is particularly suited for antiparallel bis-cystine homodimers and for heteromeric disulfides in general. We will use this classification in our review of relevant contributions to the chemistry of disulfide formation during the years 1995-1999.
