Christopher A. Alabi
Robert Frederick Smith School of Chemical and Biomolecular Engineering - Cornell University
PROteolysis TArgeting Chimeras - PROTACs
SESSION 4: PROTEIN ARCHITECTURES - STRUCTURE AND FUNCTION
Monday, June 26, 2023, at 08:55 am - 09:20 am
PROTACs have been shown to selectively induce the degradation of a wide range of intracellular proteins. By employing a ligand that recruits an E3 ubiquitin ligase and another ligand that binds a protein of interest, POI, PROTACs induce an artificial interaction between an E3 and a POI that catalyzes selective ubiquitin-tagging of the POI, leading to its proteasome-mediated degradation.1
As an alternative to small molecule- based approaches, peptide-based degraders have been developed alongside PROTACs for proteome editing in eukaryotic cells. Peptide-based PROTACs, otherwise herein referred to as PROteolysis TArgeting Peptides, PROTAP, share similar advantages to small molecule- based PROTACs with added significant advantages; they can be designed from protein structural data against any POI, and they possess large protein-protein interaction surfaces for targeting POIs for which no known small molecule ligand exists.2 One limitation, however, is that PROTAPs suffer from limited stability in biological fluids and have poor cellular permeability.
Given the advantages of peptide-based ligands over small molecules, several PROTAPs targeting highly relevant oncogenes and transcription factors have made use of a cationic cell- penetrating peptide or stapling to facilitate cellular uptake. While promising, the doses required for activity are very high, 10-100 µM, relative to small molecule PROTACs that induce degradation at doses under 200 nM.
In this presentation, I will discuss strategies to enhance the delivery PROTPs, specifically those designed against onco-targets overexpressed in various Wnt-signaling pathway-driven cancer cell lines. Collectively, I will highlight how peptide composition and formulation conditions can be precisely tuned to enhance intracellular delivery efficiency.
1. Paiva, S.-L. & Crews, C. M. Targeted protein degradation: elements of PROTAC design. Current Opinion in Chemical Biology 50, 111–119, 2019.
2. Jin, J., Wu, Y., Chen, J., Shen, Y., Zhang, L., Zhang, H., Chen, L., Yuan, H., Chen, H., Zhang, W. & Luan, X. The peptide PROTAC modality: a novel strategy for targeted protein ubiquitination. Theranostics 10, 10141–10153, 2020.
Christopher A. Alabi's expertise lies in sequence-defined oligomers, drug delivery, antibacterial agents, intracellular probes, programmable materials, and change antibacterial agents to targeted antibiotics.
His research focuses on synthetic methods for the assembly of sequence-defined oligomers, development of macromolecular antibacterial and cell penetrating agents, sequence-structure-function relationships, design and development of intracellular probes for measuring organelle specific enzyme kinetics, and assembly of new sequence-defined macromolecules that can be used to create stimuli-responsive materials