This article has been reviewed according to Science X's editorial process and policies. Editors have highlighted the following attributes while ensuring the content's credibility: Researchers at the Wyss Institute at Harvard University, Boston Children's Hospital, and Harvard Medical School (HMS) have developed FIND, a drug discovery platform that searches large libraries for molecules that modulate binding interactions between two proteins. FIND uses DNA nanoswitches to select drug candidates based on their effects on these protein-protein interactions, rather than simply whether they bind to a single target protein, giving it a key advantage over conventional binding-based screening.
In a study published in Science, the researchers used FIND to discover both small molecules and nanobodies, small antibody-like proteins, that promoted particular protein-protein interactions with relevance for different disorders. Proteins often work by binding to other proteins, and changes in these interactions can contribute to disease. Such protein interactions are also targeted by some of the most successful drugs.
For example, the diabetes drug Ozempic mimics the natural GLP-1 hormone and activates its receptor, helping regulate blood sugar and reduce appetite; and inhaled albuterol activates beta-2 adrenergic receptors on airway muscle cells, triggering signals through associated G proteins that relax these muscles and open the airways. Many conventional drug screens test compounds individually in multiwell plates, with instruments measuring changes in purified proteins or cells. Pooled screens of encoded compound libraries can search much larger collections, but most conventional methods only identify molecules that bind to a target.
"Our idea was to build each experiment onto a single DNA molecule, so that many experiments could run in parallel in one tube," said senior author Wesley Wong, Ph.D., an associate faculty member at the Wyss Institute, associate professor at HMS, 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, short for Functional Interaction-based Nanoswitch Discovery, builds on DNA nanoswitches, a technology that Wong's group first developed for single-molecule measurements and then adapted into a gel assay in 2015. Wong, who co-leads the Wyss Institute's Molecular Robotics Initiative, and co-first authors Clinton Hansen, Ph.D., and Mark Lipstein, Ph.D., subsequently advanced the technology for drug discovery with other scientists at the Wyss Institute.
DNA nanoswitches are programmable devices made from long strands of DNA. They switch between a linear shape, in which two attached potential protein partners are unbound, and a looped shape, in which the two proteins bind and bring two points on the DNA together. Compounds that promote this interaction increase the fraction of looped nanoswitches.
The team separated these shapes using gel electrophoresis, a standard laboratory method for distinguishing pieces of DNA with different sizes and structures. Looped nanoswitches moved more slowly through the gel than linear ones, allowing them to be collected separately. To develop FIND, the team attached a candidate drug molecule to each nanoswitch using a flexible linker, along with a nucleic acid barcode that identified the candidate.
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