StaPLs: versatile genetically encoded modules for engineering drug-inducible proteins

Robust approaches for chemogenetic control of protein function would enable many biological applications. We describe stabilizable polypeptide linkages (StaPLs) based on hepatitis C virus protease. StaPLs undergo autoproteolysis to cleave proteins by default, while protease inhibitors prevent cleavage and preserve protein function. We created StaPLs responsive to different clinically approved drugs to bidirectionally control transcription with zinc-finger-based effectors, and used StaPLs to create single-chain drug-stabilizable variants of CRISPR/Cas9 and caspase-9.