Bifunctional Peptide Nanofibrils for Targeted Protein Degradation

• Published in: Angewandte Chemie International Edition 2024-01, Vol.63 (3), p.e202316581-n/a
• Main Authors: Lin, Zongtao, Garcia, Benjamin A., Lv, Dongwen
• Format: Article
• Language: English
• Subjects: Ablation; Biodegradation; Cancer; Cancer therapies; Chemical synthesis; Chimeras; Degradation; Ligands; Nanofibril; Peptides - metabolism; PROTAC; Proteins; Proteolysis; Self-Assembly; Targeted Protein Degradation; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - metabolism
• ISSN: 1433-7851; 1521-3773; 1521-3773
• DOI: 10.1002/anie.202316581

Proteolysis targeting chimera (PROTAC) is a state‐of‐the‐art technology for ablating undruggable targets. A PROTAC degrader achieves targeted protein degradation (TPD) through the simultaneous binding of a protein of interest (POI) and an E3 ligase to form a ternary complex. A nanofibril‐based PROTAC strategy to form a polynary (E3)m : PROTAC : (POI)n complex has not been reported in the TPD field up to this point. A recent innovation shows that a POI ligand and E3 ligase ligand don't have to be within a fused degrader molecule. Instead, they can be recruited to cellular proximity by a self‐assembly‐driving peptide and click chemistry. The resulting nanofibrils can recruit multiple POI and E3 ligase molecules to form a polynary complex as a degradation center. The so‐called Nano‐PROTAC provides a novel approach for TPD in cancer therapy. A new PROTAC (proteolysis targeting chimera) method, reported by Zhang et al., uses self‐assembling peptides as carriers of POI (protein of interest) and E3 ligase ligands. Cellular nanofibrils built upon the peptide assembly can serve as degradation centers (Nano‐PROTACs) through the formation of polynary POI:Nano‐PROTAC : E3 complexes. This strategy has the potential to overcome the hook effect of traditional PROTACs.