Modulating protein-protein interactions: the potential of peptides

Protein-protein interactions (PPIs) have emerged as important and challenging targets in chemical biology and medicinal chemistry. The main difficulty encountered in the discovery of small molecule modulators derives from the large contact surfaces involved in PPIs when compared with those that participate in protein-small molecule interactions. Because of their intrinsic features, peptides can explore larger surfaces and therefore represent a useful alternative to modulate PPIs. The use of peptides as therapeutics has been held back by their instability in vivo and poor cell internalization. However, more than 200 peptide drugs and homologous compounds (proteins or antibodies) containing peptide bonds are (or have been) on the market, and many alternatives are now available to tackle these limitations. This review will focus on the latest progress in the field, spanning from "lead'' identification methods to binding evaluation techniques, through an update of the most successful examples described in the literature.