Chapter 7: RaPID Discovery of Macrocyclic Peptide Inhibitors of Protein–Protein Interactions

Protein–protein interactions (PPIs) are common modulators of biological systems and many of these interactions are prime targets for the development of future therapeutics and diagnostics. Discovering compounds that interfere with PPIs has, however, proven difficult as these interactions often occur over large, well attuned surfaces, making it near impossible for small ligands to disrupt. In this chapter we will discuss the Random non-standard Peptide Integrated Discovery platform (RaPID), an mRNA-based, in vitro screening system that allows for the discovery of potent macrocyclic peptide ligands from a massive 10¹³ member randomized library. The products of RaPID, as illustrated by three case studies, often bind strongly, with low nM affinities, to allosteric binding pockets of the protein target, yielding high-potential peptide drug candidates against previously considered undruggable PPIs.