Photoswitchable DNA-Encoded Libraries: A Discovery Platform for Light-Controlled Protein Binders

Researchers from the University of Utah are developing a new way to discover molecules whose activity can be controlled by light. Such molecules allow scientists to turn biological processes on and off with high precision, making them valuable tools for studying how living systems work and for developing new biotechnology applications. Today, discovering these molecules is slow because researchers must design and test one candidate at a time, generally requiring detailed information about the target protein. Because many important proteins currently lack suitable light-controlled probes, this bottleneck limits the ability of researchers to study biological processes with spatial and temporal precision. The research team will overcome this challenge by adapting DNA-encoded libraries, a technology that allows millions of different molecules to be tested simultaneously, to the discovery of light-responsive compounds. Their work could establish a faster and more broadly applicable method for discovering light-controlled molecules, expanding the number of biological targets that can be studied and advancing biotechnology. By making probe discovery faster and less dependent on prior structural knowledge, the project could help U.S. scientists investigate a wider range of biological systems and develop new biotechnology applications. The project applies the approach to the discovery of light-controlled affinity tags and provides datasets that can support future machine-learning efforts, thus directly addressing national priorities in biotechnology and artificial intelligence. The project will also provide broader impact by creating an openly accessible molecular discovery platform, training students in advanced research technologies, and establishing an industry mentoring network to help prepare the next generation of scientists. The project will develop DNA-encoded libraries composed of light-responsive molecules and establish methods for identifying light-controlled protein binders by comparing affinity selections performed under controlled experimental conditions. Fundamental studies will determine how library design influences discovery success and establish principles for effective library construction. The project will also create an openly accessible library containing approximately one million compounds, together with standardized selection protocols and data analysis tools, enabling researchers across the United States to apply this technology to their own biological targets. Finally, the approach will be demonstrated by discovering light-controlled protein binders that can be developed into reversible affinity tags for biotechnology applications. Together, these studies will establish the scientific and technical foundation for broadly applying this technology to photopharmacology. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.