Design and Synthesis of Small Molecules to Target Protein-Protein Interactions

Abstract

Protein-protein interactions (PPIs) play key regulatory roles in biological systems, and some of these are interesting drug targets. Consequently, it is important to develop generally applicable methods to identify small molecules that disrupt or disturb PPIs. One emerging approach is to use novel small molecule scaffolds to mimic protein-protein interfaces. To identify good mimics for PPI targets, a novel computational approach Exploring Key Orientations (EKO) has been developed. This thesis is focused on the design, synthesis, EKO analysis and biological applications of two interface mimic scaffolds.

The first mimic, an oligo-piperidine-piperidinone (OPP) scaffold was designed and synthesized to target extended interface regions. Derivatives of this scaffold have been efficiently prepared in a divergent-convergent method. Conformational studies revealed that the OPP scaffold could exist in an extended helical conformation and it was a good mimic of ideal α-helix in solid state. Further investigations by molecular modeling indicated this scaffold could be a multi-faceted mimic for several secondary structure motifs in solution. An interesting protein target called antithrombin was discovered with EKO database mining analysis for the OPP scaffold. In biological studies, derivatives of OPP were found to interfere with oligomerization of antithrombin in a side-chain and concentration dependent manner.

As an orthogonal interface mimic, a new constrained cyclic peptide-organic hybrid was also explored to target compact PPI interface regions. An anthranilic acid was incorporated in the scaffold as a turn-inducing motif. Extensive conformational analyses by 1D and 2D NMR, CD, and molecular modeling were performed and the results showed that the cyclic peptide scaffold could mimic multiple turn structures. Moreover, these new turn mimics were conformationally homogeneous in solution and their conformations had a strong and predictable correlation with side-chain stereochemistries.

The scaffolds described in this thesis represent suitable scaffolds to target protein-protein interactions. Compared with traditional methods, interface mimicry approach together with EKO analysis can significantly facilitate the discovery of small molecules for protein-protein interactions.