Disulfide Bond Mimetics: Strategies and Challenges

The activity profile of many biologically relevant proteins and peptides often relies on a precise 3D structural organization. In this context, disulfide bonds are natural covalent constraints that play a key role in driving and stabilizing the folding pattern of these molecules. Despite its prominent significance as structural motif, the disulfide bond itself is inherently unstable under physiological conditions, posing a major limit to the use and development of disulfide-rich peptides and proteins as molecular tools and drug lead compounds. To tackle this restriction, disulfide engineering with stable functional analogues has arisen a considerable interest. Here, the most popular approaches to disulfide replacement are reviewed and discussed with particular emphasis on advantages and limitations under both functional and synthetic perspectives.