Events

Delivery of Peptide-Based Targeted Protein Degraders

Molecular degraders are becoming ubiquitous in chemical biology research given their proven ability to selectively degrade a diverse array of intracellular proteins. This process is achieved by employing a heterobifunctional ligand with one end that recruits an E3 ubiquitin ligase and another that binds to the protein of interest (POI). These compounds catalyze the selective ubiquitin-tagging of the POI, ultimately resulting in the proteasome-mediated degradation of the target protein. In addition to conventional small-molecule based approaches led by class of molecules known as PROteolysis Targeting Chimeras (PROTACs), there has been a slow but steady development of peptide-based degraders, which we refer to as PepTACs, for proteome editing within eukaryotic cells. PepTACs offer many advantages similar to small molecule-based PROTACs, with the added benefit of being designed based on protein structural data for any desired POI. Moreover, peptides cover an extensive protein interaction surface, which is particularly advantageous for targeting POIs lacking known small molecule ligands. However, PepTACs face significant limitations, such as limited stability in biological fluids and poor cellular permeability. In this presentation, I will discuss new strategies developed in my research lab to enhance the intracellular delivery PepTACs, specifically those designed against onco-targets overexpressed in various Wnt-driven cancer cell lines. Collectively, I will highlight how peptide composition and formulation conditions can be precisely tuned to enhance intracellular delivery efficiency.

Hosted by Professor Jason Zhang