A Boston research team has built a drug-discovery platform that uses DNA nanoswitches to pick compounds based on how they reshape protein-protein interactions, not just whether they bind one target. The Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston Children’s Hospital and Harvard Medical School described the approach, called FIND (Functional Interaction-based Nanoswitch Discovery), in a Nov. 5 release.
The study appears in Science. Senior author Wesley Wong led the work with co-first authors Clinton Hansen and Mark Lipstein.
How FIND works
Traditional screens often look for molecules that stick to a single protein. FIND instead uses DNA nanoswitches that report whether a candidate changes how two proteins interact. That functional readout can surface compounds that promote or disrupt partnerships that matter in disease.
The team applied FIND to PPAR-gamma, a well-known diabetes target, using a DNA-encoded library with about 400 million members. The screen recovered compounds that promote PPAR-gamma’s interaction with a fragment of the coactivator CBP and that increased lipid accumulation in cells, according to the Wyss Institute.
Beyond diabetes targets
FIND also turned up a nanobody that modulates the interaction between the SARS-CoV-2 spike protein and its receptor. As a further check, the platform recovered a known activator of the beta-2 adrenergic receptor, supporting the method’s ability to find functionally relevant hits.
Researchers looking for background on drug discovery methods and DNA nanotechnology will find the platform sits at the intersection of molecular engineering and pharmacology.
Startup license and support
The technology has been licensed to a newly formed startup co-founded by members of the research team, the Wyss Institute said. Support came from the National Institutes of Health, the Wyss Institute, Boston Children’s Hospital, Takeda, the Beckman Foundation and other funders.
For Boston’s Longwood medical area, FIND adds another local tool aimed at shortening the path from library screens to immunology and metabolic drug leads.