Macrocyclic peptides are the prevalent way to mimic interface helices for disruption of protein interactions, but current strategies to do this via synthetic C-cap mimics are underdeveloped and suboptimal. Bioinformatic studies described here were undertaken to better understand Schellman loops, the most common C-caps in proteins, to design superior synthetic mimics. An algorithm (Schellman Loop Finder) was developed, and data mining with this led to the discovery that these secondary structures are often stabilized by combinations of three hydrophobic side chains, most frequently from Leu, to form hydrophobic triangles. That insight facilitated design of synthetic mimics, bicyclic Schellman loop mimics (BSMs), where the hydrophobic triumvirate was replaced by 1,3,5-trimethylbenzene. We demonstrate that BSMs can be made quickly and efficiently, and are more rigid and helix-inducing than the best current C-cap mimics, which are rare and all monocycles.
