α-Helices play a critical role in mediating protein-protein interactions (PPI) as recognition motifs. Since a-helix-mediated PPIs are involved in many important biological pathways, there is a great interest in developing synthetic α-helix mimetics as PPI modulators. Such α-helix mimetics would have great potential as invaluable research tool to delineate protein functions, as well as therapeutic candidates. A number of α-helix mimetic molecules have been reported, which include miniproteins, stabilized helical peptides, and helical foldamers. An alternative approach is to develop small-molecule-based a-helix mimetics (e.g., terphenyl-based α-helix mimetics). In contrast to peptide-based molecules, small-molecules may have advantages, such as good cell permeability, proteolytic stability, and low production cost. In the last decade, many terphenyl-inspired α-helix mimetic small-molecules have been developed. Typically, these molecules have rod-like scaffolds composed of three aromatic rings, each of which is substituted with appropriate residues, enabling them to mimic 3-dimensional arrangement of critical side chains in α-helical peptides. While the feasibility of these terphenyl-based molecules as inhibitors of α-helix-mediated PPIs has been demonstrated, their potency has yet to be improved. Here we report a strategy to improve the potency of α-helix mimetic small-molecules. Inspired by the stapled peptide approach, we incorporated a hydrocarbon bridge into α-helix mimetic small-molecules. Therefore, the resulting molecules have a bridge on the one side and three key residues for protein binding on the other side. This hydrocarbon bridge would provide a significant conformational rigidity by restricting the rotation of three aromatic rings in the terphenyl-like scaffolds. As anticipated, the stapled α-helix mimetic small-molecules showed enhanced binding affinity to the target protein, compared to the parent single-face a-helix mimetics.

Stapled α-helix mimetic small-molecules

251st National Meeting (2016)

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