Peptide constraining and scaffold grafting for protein mimetics design: lessons from the p53-hDM2 interaction

Peptides are promising candidates for targeting unconventional drug targets involving large interaction interfaces, such as protein-protein interactions (PPIs), historically considered undruggable. However, when removed from their native protein context, short peptides are flexible, resulting in an entropic penalty upon binding and poor pharmacological properties. A wide variety of design strategies have therefore been developed, making the selection of the most appropriate protein mimicry approach far from trivial. In this review, we provide an overview of the main approaches, focusing on the well-established p53-hDM2 interaction, which has been widely used as a model system in the field. This model enables a direct comparison between the different design strategies and highlights their respective impact on conformational stability, target affinity, and pharmacological properties, including proteolytic stability, cell permeability, and toxicity, ultimately governing biological activity. Overall, this comparison aims to guide the rational selection of design strategies for the development of new proteomimetics targeting challenging PPIs.