bioPROTACs as versatile modulators of intracellular therapeutic targets including proliferating cell nuclear antigen (PCNA)

Significance Intracellular proteins interact with each other to perform functions that are critical to normal and disease states. Attempts at altering pathological protein–protein interactions with traditional approaches have largely failed. Here, we explore an emerging approach we call “bioPROTACs”—engineered fusion proteins that consist of a target binding domain and an E3 ligase, an arrangement that results in the specific degradation of the therapeutic target. Our systematic study shows bioPROTAC design requirements are highly flexible in terms of both the binding domain and E3 ligase components. Resulting molecules can be used as powerful tools for uncovering biology, informing on the design of small molecule target degraders (e.g. PROTACs), and, if delivery issues can be addressed, potential therapeutics.