David MacMillan: A “flashlight” to identify cellular proteins for drug discovery

Oct. 6, 2020

A technology for illuminating proteins on the cell surface promises to boost the success of drug discovery, aid in basic research, and may even assist in finding antiviral treatments for COVID-19.

The ability to “see” proteins in the neighborhood around drug receptors and other cell-surface proteins could help reduce the risk of unforeseen biological interactions that lead to toxicity or side effects. The technique, known as MicroMap (μMap), acts like a flashlight that can illuminate the identities of proteins. It does this using a photocatalyst, a molecule that when activated by light spurs a chemical reaction. The photocatalyst — in this case, an organic metal compound — can be configured to attach to any one of some 40,000 proteins on a cell’s surface.

The technique identifies the 10 or 15 nearest protein molecules by converting the protein of interest — the drug receptor, for example — into a kind of antenna. When researchers shine blue light on the cell, the antenna converts the light’s energy into chemical energy, which in turn activates the formation of fluorescent carbenes that attach to nearby proteins, making them visible. The team is collaborating with researchers in the Princeton Department of Molecular Biology to explore this technology for understanding proteins near the spike protein of COVID-19.

To make it easier for the technology to be adopted, the researchers created a spinout company, Dexterity Pharma LLC, to produce kits containing the needed chemical reagents. The goal is to lower the barrier to entry for chemical biologists to incorporate μMap into their studies.

"We are now able to label things within a very short distance of a protein we are studying. And that’s never been done before.” – David MacMillan

Innovator: David MacMillan, the James S. McDonnell Distinguished University Professor of Chemistry

Co-inventor: Postdoctoral research fellow Jacob Geri

Collaborators: Princeton visiting fellow Aaron Trowbridge, postdoctoral research associate
Ciaran Seath, and graduate students Benito Buksh, Beryl Li and James Oakley; Merck & Co.
scientists Olugbeminiyi Fadeyi, Erik Hett, Stefan McCarver, Rob Oslund, Dann Parker, Tamara
Reyes-Robles, Frances Rodriguez-Rivera, Keun Ah Ryu, Adam Schwaid, Paul Tawa, Tao Wang and Cory White; Dexterity Pharma Chief Scientific Officer Joel Austin

Development status: The technology has been patented and licensed exclusively to Dexterity Pharma LLC.

Funding: National Institutes of Health, National Science Foundation, Princeton Faculty
New Ventures Assistance Fund and Merck & Co.

Learn more:

For licensing enquiries, contact Laurie Tzodikov, Assistant Director, Office of Technology Licensing.

David MacMillan lab group

David MacMillan (far right) and his research team are developing a technology that lights up proteins near drug receptors. Photo by C. Todd Reichart