Peptides have emerged as a therapeutically and commercially important class of drugs offering the advantage of greater specificity, potency and lower toxicity over small molecule pharmaceuticals. More importantly, peptides have proven to be invaluable research tools helping to dissect physiological functions of many human receptors and elucidating the biological mechanism underlying diseases. Potency and selectivity are often encoded in secondary structural motifs that are stabilised within the tertiary structure of larger proteins or through disulfide bonds in peptides. Particularly venomous animals excel in using the latter strategy to produce complex cocktails of highly potent and selective venom peptides through highly conserved cysteine frameworks that fold into scaffolds to correctly display the pharmacophore while at the same time providing protection against enzymatic degradation.
Our laboratories have a strong interest in developing chemical methodologies to improve, simplify and control disulfide bond formation as well as to investigate disulfide bond mimetics that could convey greater stability or simplify the folding complexity when multiple disulfide bonds are present. Here we present an overview on the importance of disulfide bonds, the most commonly used methodologies to direct folding, disulfide bond mimetics that retain full activity and selectivity, and innovative concepts that facilitate synthetic access to more complex disulfide-rich peptides as well as medium-sized libraries. We exemplify these concepts with different neuropeptides and venom peptides including structural, pharmacological and stability data.