Supramolecular polymers for targeted protein degradation

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Project Summary Vision: Recent advances in targeted protein degradation strategies such as hydrophobic tagging (HyT) and proteolysis targeting chimeras (PROTACs) have the potential to revolutionize therapeutic development as we know it. This is provided that these strategies can overcome the translational challenges of targeted delivery, improved specificity and cellular internalization. This project outlines two strategies to couple these advanced synthetic biology techniques with novel supramolecular polymers to address these significant hurdles currently facing the field. Supramolecular polymers provide the opportunity to enhance cellular internalization, provide dynamic presentation of protein binding ligands and provide the potential for multivalent, and in turn higher affinity, binding interactions with target proteins. The success of this project could unlock a vast array of new drug targets, previously thought to be undruggable, while circumventing the reliance on small molecule therapeutics and their associated problems with drug resistance. This project will investigate the opportunity of dynamic supramolecular polymers as a strategy to enhance the efficacy of targeted protein degradation therapies The misfolding or misregulation of proteins has been shown to lead to the development of many diseases including neurodegenerative diseases, cancers and fibrotic disorders. Small molecule drugs, designed to inhibit protein function is the current gold standard in the vast majority of clinically-used therapeutic agents available. However, to achieve clinically relevant protein inhibition, greater than 90% target binding is required, resulting in high dosing levels that can result in off-target effects. Further, these approaches are only suitable when the protein target has an active binding site suitable for inhibition. What about the proteins that don’t have an active binding site or contribute to disease through other mechanisms? What if there was another way to not just inhibit but to selectively degrade these aberrant proteins as a therapeutic strategy? We feel this can be achieved with supramolecular polymers designed to achieve targeted protein degradation. To demonstrate the potential and principle of supramolecular polymer targeted protein degraders, we will address the following two specific aims: (1) To synthesize and characterize biocompatible supramolecular polymers capable of self-assembly into nanostructures coupled with achieving degradation through a hydrophobic tagging approach of a protein of interest, (2) Demonstrate efficacy of a multifunctional supramolecular PROTAC polymer capable of self-assembly, cell internalization, targeting and subsequent degradation of a protein of interest.