Researchers at Harvard and Boston Children’s Hospital have developed a high-throughput drug screening platform that identifies molecules capable of changing how proteins interact. A study published today in Science demonstrates the platform’s potential through the discovery of both small molecules and nanobodies capable of promoting specific protein-protein interactions associated with different disorders.
Protein-protein interactions play an essential role in many biological processes, and are therefore important targets for existing medicines. For example, the diabetes drug Ozempic (semaglutide) mimics the GLP-1 hormone to activate its receptor, while inhaled albuterol activates beta-2 adrenergic receptors to relax airway muscles. However, identifying compounds that modify these interactions remains challenging with conventional screening approaches.
The new screening platform, called FIND (Functional Interaction-based Nanoswitch Discovery), uses DNA nanoswitches to screen large molecular libraries for compounds that alter interactions between proteins. Unlike conventional drug screening methods, which typically identify molecules that bind to individual proteins, FIND selects drug candidates based on their ability to influence how two proteins interact.
“Our idea was to build each experiment onto a single DNA molecule, so that many experiments could run in parallel in one tube,” said Wesley Wong, PhD, associate faculty member at the Wyss Institute, associate professor at Harvard Medical School, and investigator at Boston Children’s Hospital. “This gives us a high-throughput way to search for molecules that change how proteins work together.”
FIND builds on DNA nanoswitch technology originally developed by Wong’s research group for single-molecule measurements. These programmable devices consist of long DNA strands that switch between two configurations. When two attached proteins bind to one another, the DNA strand forms a loop, allowing researchers to identify the protein pair based on the barcode encoded into the DNA.
“Each candidate stays linked to the result of its own experiment,” said Mark Lipstein, PhD, postdoctoral fellow in Wong’s group. “We can then separate the nanoswitches by their response and sequence the barcodes to identify the molecules that were selected.”
The team used FIND to screen a library of 400 million small molecule drugs targeting PPAR-gamma, a protein involved in regulating insulin sensitivity and fat storage. This allowed them to identify compounds that promote PPAR’s interaction with a fragment of its partner protein, CBP, activating the protein. Following the same approach, the researchers identified a nanobody that modulates the interaction between the SARS-CoV-2 spike protein and its receptor on human cells.
“We can directly search for molecules that have the effect we want on a disease-related protein-protein interaction,” said Clinton Hansen, PhD, instructor at Harvard Medical School. “The molecules we find could become starting points for developing new medicines or useful research tools for understanding diseases.”
While further development will be needed, FIND’s potential for drug discovery is already attracting commercial interest. The technology has been licensed to a newly formed startup co-founded by members of the research team, which will pursue its development as a high-throughput tool for discovering drug candidates that conventional discovery tools have struggled to reach.
