Proc. Natl. Acad. Sci. USA 111, 11007–11012 (2014)

Finding compounds that can modulate protein-protein interactions (PPIs) or protein misfolding defects is challenging owing in part to the large, featureless surfaces that need to be targeted. Several strategies exist—for example, using peptidic or nonpeptidic α-helix mimics to modulate PPIs—but the solubility and synthetic methods for these molecules have limited their utility. To overcome some of these barriers, Oh et al. developed a synthetic strategy to generate a one-bead one-compound library of nonpeptidic α-helix mimics based on a triazine-piperazine-triazine scaffold whose side chains could be modified to promote better hydrophilicity. Specifically, the authors first added a peptoid-encoding component to the beads and subsequently performed high-throughput screens against MCL-1, an antiapoptotic member of the BCL-2 family of proteins that has been implicated in various cancers, and against α-synuclein, whose misfolding is implicated in Parkinson's disease. The MCL-1 screen found several compounds that bind MCL-1 and inhibit its known functional interaction with a BH3 helical peptide in vitro and its interaction with BAK in vivo. One of these compounds was predicted by in silico docking to mimic the binding mode of the BH3 peptide. The α-synuclein screen found two hit compounds that bind α-synuclein and decrease its aggregation propensity. These results suggest that PPI inhibitors and protein folding modulators (collectively, 'pharmacological chaperones') against different helical proteins can be identified from α-helix mimic libraries.