Targeting Intracellular Protein-Protein Interactions with Therapeutic Peptides
Kristian Stromgaard
Professor, CEO, University of Copenhagen
Protein-protein interactions (PPIs) are essential to vital cellular processes and serve as potential targets for therapeutic intervention. We are particularly interested in the PPIs between integral membrane protein receptors and their intracellular protein partners, so-called ‘receptor complexes’ and examine how modulation of PPIs of such receptor complexes can provide novel biological insight and new therapeutics. Several of these PPIs are located intracellular, and often in the central nervous system. So, the therapeutic peptides need to cross cell membranes and the blood-brain barrier. We have performed a thorough examination of different combinations of cell-penetrating peptides (CPPs) and peptides cargo. In one case, we have developed peptide-based inhibitors of the PSD-95/glutamate receptor interaction, as potential treatment for acute ischemic stroke. Specifically, we have exploited that PSD-95 contains a tandem PDZ1-2 domain and have designed and synthesized dimeric peptides with low nanomolar affinities and have demonstrated that these ligands are potential treatment for ischemic stroke. The lead compound AVLX-144 was recently successfully examined in a Phase I clinical trial.