Discovering molecular modulators with nanoswitch screening

Molecules that modulate protein-protein interactions, including through ternary complex formation, have been established as key therapeutics. Yet they can be challenging to discover, as standard screening approaches often lack throughput or fail to directly assay multibody interactions. We addressed this by combining DNA nanoswitch-based selection of nucleotide-encoded libraries with next-generation sequencing to create FIND (Functional Interaction-based Nanoswitch Discovery), which enables ultrahigh-throughput discovery of compounds that induce or increase protein-protein interactions. We demonstrate FIND by discovering nanobodies that stabilize the interaction between angiotensin-converting enzyme 2 and the receptor-binding domain of severe acute respiratory syndrome coronavirus 2 and by discovering agonists of peroxisome proliferator-activated receptor gamma from a DNA-barcoded small-molecule library. By enabling rapid discovery of molecular modulators, FIND could lead to new therapeutics across many conditions.