Rational development of selective regulators of protein-protein interactions and their therapeutic applications

Protein-protein interactions (PPIs) are intimately involved in almost all biological processes, including inter- and intracellular signal transduction, gene expression, cell proliferation, and apoptosis. Therefore, they are important phenomena in basic research and promising targets for treating human disease. Nevertheless, targeting PPIs is challenging, as PPI interfaces are large, flat, and are usually endowed with a significant degree of conformational flexibility.

Peptides are ideal candidates for targeting PPIs as they have demonstrated high conformational flexibility, and high selectivity. Importantly, peptides derived from PPI sites can mimic the interaction site of one of the proteins, serving as competitive inhibitors (antagonists) of the respective interaction and explore its consequences. Thus, it is not surprising that peptides are becoming increasingly recognized as useful pharmacological tools for basic research and for drug discovery, with over 60 peptide-based drugs.

Mitochondria play central roles in maintaining cellular metabolic homeostasis, cell survival and cell death. They are also the so-called "powerhouses" of cells as they produce most of the cellular ATP. The major mechanisms by which mitochondria maintain their homeostasis are mitochondrial quality control mechanisms such as mitophagy and mitochondrial dynamics including both fission and fusion.

Using a rational approach, we developed peptides that target specific PPIs and regulate mitochondrial homeostasis in a specific manner. Results from our studies indicate that modulating PPIs using peptides offers the potential of highly selective targeting of individual enzymes while differentiating between similar proteins, with high specificity and low toxicity.