Sean Davies awarded Scaling Success grant to develop small molecules with promise of protecting against cardiometabolic disease

Sean Davies (Vanderbilt University)

Sean Davies, associate professor of pharmacology and associate director of graduate studies for the department, has been awarded a Scaling Success grant from Research Development and Support in the Office of the Vice Provost for Research and Innovation.

The funding injection for the project, titled “Development of small molecule NAPE-PLD activators,” will ultimately help Davies and his collaborators, Gary Sulikowski, Alex Waterson, and Musawwir Alli-olwafuyi, pursue further support from the National Institute of General Medical Sciences.

NAPE-PLD is an enzyme that produces molecules beneficial for resolving inflammation and protecting against cardiometabolic diseases, including heart attack, stroke, diabetes, insulin resistance, and non-alcoholic fatty liver disease. Its levels are diminished in such diseases, indicating that substances that activate NAPE-PLD could serve as potential treatments. Using a high-throughput screen of 40,000 compounds, Davies and his collaborators have pinpointed potential activators that share a similar molecular framework.

Resources from the Scaling Success grant will help the team confirm the effectiveness of these compounds, understand their interactions with NAPE-PLD, and explore how they function. These initial findings are crucial for securing external funding for a comprehensive study to confirm the therapeutic value of stimulating NAPE-PLD activity.

“Realization of our long-term goal of developing small molecule NAPE-PLD activators for use as molecular probes and therapeutics in vivo will require a full-fledged medicinal chemistry campaign to identify more potent, drug-like properties and target-selective lead compounds,” Davies said. “Successful completion of the studies we will conduct will be an important stepping stone to that external funding.”

An expert on NAPE-PLD and the N-acyl-ethanolamine biosynthetic pathway, Davies will direct the overall project. Postdoctoral fellow Alli-olwafuyi will carry out cellular and mass spectrometry assays. Sulikowski, the Stevenson Professor of chemistry, professor of pharmacology, and director of the Vanderbilt Institute of Chemical Biology, will help interpret the experimental results and perform concentration response curves for in vitro biochemical NAPE-PLD activity within the . Waterson, research professor of pharmacology and chemistry and associate director of drug discovery at VICB, will interpret experimental results to develop a more highly refined medicinal chemistry plan. Additional collaborators include Amanda Doran, assistant professor of molecular physiology and biophysics and medicine, and Lars Plate, assistant professor of chemistry and biological sciences.

Scaling Success Grants support faculty as they scale up to increasingly impactful team research, scholarship, and creative works, including larger awards from external sponsors. The program specifically supports faculty with projects that have already generated interest and encouragement from a federal, foundation, or industry sponsor for the purpose of further developing the project or team prior to formal submission to the sponsor. Scaling Success facilitates a stronger proposal and increases the possibility of a significant external award relative to the lead investigator’s own discipline and award history.