SHAPPI · Scaffold hybridization approach targeting PPIs

Scaffold hybridization approach targeting PPIs

Protein-protein interactions (PPIs) control all cellular processes relevant to health and disease, hence an outstanding challenge in chemical biology is to develop generic approaches for PPI inhibition. Such inhibitors represent unique tools to understand biological processes and starting points for drug discovery, for treatment of multiple illnesses for which effective treatments don’t currently exist e.g. cancer. Proteins recognize each other through a large, shallow, less well-defined interaction interface. Key amino acids (termed hot-spots) are responsible for the majority of the binding energy, however these tend to be similar for different PPIs, thus selective PPI inhibition particularly in related protein families is challenging. Small molecules would be ideal therapeutics, but tend to be unsuccessful against larger, more challenging interfaces. An alternative approach to target these interfaces is the use of peptidomimetics or proteomimetics. These structures consist of non-natural building blocks capable of mimicking the 3D conformation required for bioactivity or reproducing the spatial projection of the functionality required for protein recognition. These scaffolds are generally suitable to target helix mediated interactions but targeting β-sheet mediated PPIs is still a significant challenge. Several therapeutically relevant β-sheets are known, however conventional drug design tends to be unsuccessful, thus new methodologies are needed. We hypothesized that using peptide-small molecule hybrids, where the peptide could act as an anchor on the protein surface directing the small molecule fragment toward a specific binding site could result in improved ligands for such interactions. The fellowship focussed on inhibiting challenging PPIs using different peptidomimetic, proteomimetic, and peptide-small molecule hybrid structures (Figure 1). The objectives were to design and synthesize peptidomimetic/proteomimetic and hybrid structures and characterize their binding and structural features in order to develop generic approaches suitable for PPI inhibition.

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