Background: Interactions between proteins play a key role in nearly all cellular process,
and therefore, its dysregulation may lead to many different types of cellular dysfunctions. Hence,
pathologic Protein-Protein Interactions (PPIs) constitute highly attractive drug targets and hold
great potential for developing novel therapeutic agents for the treatment of incurable human diseases.
Unfortunately, the identification of PPI inhibitors is an extremely challenging task, since
traditionally used small molecules ligands are mostly unable to cover and anchor on the extensive
and flat surfaces that define those binary protein complexes. In contrast, large biomolecules such as
proteins or peptides are ideal fits for this so-called “undruggable” sites. However, their poor pharmacokinetic
properties have also limited their applications as therapeutics. In this context, peptidomimetic
molecules have emerged as an alternative and viable solution to this problem, since they
conserve the architectural and structural features of peptides and also exhibit substantially improved
Conclusion: In the last decades, a wide array of chemical approaches granting access to conformationally
constrained peptides with substantially improved pharmacokinetic profiles have been described,
with a special focus on those affording stapled peptides and allowing large-scale macrocyclizations.
These peptidomimetic molecules have been successfully applied to target a plethora of
biological hosts, which highlights their promising future as novel therapeutics for the treatment of
incurable human diseases.