Development of a chemically induced dissociation system via phage surface‐displayed nanobody screening

Chemical methods for controlling protein function posttranslationally in an inducible manner provide profound insights into cellular processes and are powerful tools in synthetic biology. Here, we utilized the phage display method to screen for a nanobody whose interaction with the hepatitis C virus protease NS3a can be disrupted by FDA-approved small-molecule drugs. By employing Grazoprevir as a chemical disruptor of the NS3a/nanobody interaction, we demonstrate that our chemically induced dissociation system (CIDiss) can effectively regulate protein-protein interaction in the endoplasmic reticulum in human cells. This CIDiss system offers a valuable tool for synthetic biology, with potential for enhanced safety in cell-based therapies. Impact statement Here, we describe a novel chemically-induced dissociation (CIDiss) system which can effectively and safely regulate protein-protein interaction in the endoplasmic reticulum in human cells. This enhances the safety profile of cell-based therapies, which has potential for medical applications and also offers a versatile tool for dissecting and modulating protein-protein interactions.