Formation of Disulfide Bonds in Synthetic Peptides and Proteins

Disulfide bridges play a crucial role in the folding and structural stabilization of many important extracellular peptide and protein molecules, including hormones, enzymes, growth factors, toxins, and immunoglo-bulins (1–10). In addition, the artificial introduction of extra disulfide bridges into peptides or proteins allows the creation of conformational constraints that can improve biological activity (11–15) or confer ther-mostability (5, 16–19). Given this intrinsic biological interest, disulfide-con-taining peptides have long been attractive targets for chemical synthesis. Starting with the pioneering work of du Vigneaud on oxytocin (20), the challenge to reproduce and engineer increasingly complex arrays of disulfide bridges as are found in natural peptides and proteins (7, 10, 21– 23) has stimulated the efforts and ingenuities of many peptide chemists. Table 1 provides a representative, but by no means exhaustive, listing of noteworthy syntheses of peptides or small proteins with one or more disulfides. The methods can be readily generalized to analogs in which cysteine residues are replaced by homologs, such as homocysteine, or by sterically restricted derivatives, such as penicillamine (β,β-dimethylcysteine).