A major focus of our group is to develop a systematic approach for targeting protein-protein interactions with synthetic ligands. Protein-protein interactions are considered challenging targets because of the inherent difficulty in specifically recognizing large interfaces with small molecules. As part of our efforts, we have developed an algorithm (HippDB) to identify protein-protein complexes that are potentially amenable to disruption by synthetic mimics of protein secondary structures.

We have developed three classes of synthetic scaffolds (described below) that mimic helical and strand conformations. The synthesis of these scaffolds utilizes alpha amino acids and has been optimized for solid phase. Several examples in which the designed molecules can modulate intracellular protein-protein interactions have been described.

Protein Domain Mimetics:

Hydrogen Bond Surrogate Helices (image right) are stabilized alpha-helices in which one main chain i to i+4 hydrogen bond has been replaced with a carbon-carbon bond. These helices have been shown to target their protein receptors with high affinity.
Oxopiperazine Helix Mimetics (image right) are a class of nonpeptidic helix mimetics derived from amino acids. OHMs feature chiral backbones and adopt stable conformations that reproduce the arrangement of i, i+4, and i+7 residues on an alpha-helix.
Triazolamers (image right) are nonpeptidic oligomers in which the amide bonds in peptides are replaced with 1,2,3-triazole rings but the chiral main-chain and amino acid side chains are preserved.