Druggable protein–protein interactions – from hot spots to hot segments

Protein-Protein Interactions (PPIs) mediate numerous biological functions. As such, the inhibition of specific PPIs has tremendous therapeutic value. The notion that these interactions are 'undruggable' has petered out with the emergence of more and more successful examples of PPI inhibitors, expanding considerably the scope of potential drug targets. The accumulated data on successes in the inhibition of PPIs allow us to analyze the features that are required for such inhibition. Whereas it has been suggested and shown that targeting hot spots at PPI interfaces is a good strategy to achieve inhibition, in this review we focus on the notion that the most amenable interactions for inhibition are those that are mediated by a 'hot segment', a continuous epitope that contributes the majority of the binding energy. This criterion is both useful in guiding future target selection efforts, and in suggesting immediate inhibitory candidates--the dominant peptidic segment that mediates the targeted interaction.