Ligation to Scavenging Strategy Enables On-Demand Termination of Targeted Protein Degradation

Event-driven bifunctional molecules, typified by proteolysis targeting chimera (PROTAC) technology, have been successfully applied in degrading many proteins of interest (POI). Due to the unique catalytic mechanism, PROTACs will induce multiple cycles of degradation until the elimination of the target protein. Here, we propose a versatile Ligation to scavenging approach to terminate event-driven degradation for the first time. Ligation to the scavenging system consists of a TCO-modified dendrimer (PAMAM-G5-TCO) and tetrazine-modified PROTACs (Tz-PROTACs). PAMAM-G5-TCO can rapidly scavenge intra-cellular free PROTACs via an inverse electron demand Diels- Alder reaction and terminate the degradation of certain proteins in living cells. Thus, this work proposes a flexible chemical knockdown approach to adjust the levels of POI on-demand in living cells, which paves the way for controlled target protein degradation.

Automated summary

Event-driven bifunctional molecules, such as PROTAC technology, have been successfully used to degrade proteins of interest (POI). In this study, we propose a versatile ligation to scavenging approach to terminate event-driven degradation. This approach utilizes a TCO-modified dendrimer and tetrazine-modified PROTACs to rapidly scavenge intra-cellular free PROTACs and halt the degradation of specific proteins in living cells. This work presents a flexible chemical knockdown approach for controlling the levels of POI in living cells.