Small molecule protein-protein interaction inhibitors as CNS therapeutic agents: current progress and future hurdles

Protein-protein interactions are a crucial element in cellular function. The wealth of information currently available on intracellular-signaling pathways has led many to appreciate the untapped pool of potential drug targets that reside downstream of the commonly targeted receptors. Over the last two decades, there has been significant interest in developing therapeutics and chemical probes that inhibit specific protein-protein interactions. Although it has been a challenge to develop small molecules that are capable of occluding the large, often relatively featureless protein-protein interaction interface, there are increasing numbers of examples of small molecules that function in this manner with reasonable potency. This article will highlight the current progress in the development of small molecule protein-protein interaction inhibitors that have applications in the treatment or study of central nervous system function and disease. In particular, we will focus upon recent work towards developing small molecule inhibitors of amyloid-beta and alpha-synuclein aggregation, inhibitors of critical components of G-protein-signaling pathways, and PDZ domain inhibitors.