Short Report of Gregory Sliwoski: STUDYING SMALL-MOLECULE MODULATORS OF THE Y4 RECEPTOR at University of Leipzig (AUG 20 – SEPT 10)

/ October 19, 2015/ News

by Gregory Sliwoski (doctoral student at Vanderbilt University): After completing my M.S. in pharmacology from Vanderbilt University under Prof. Dr. Jens Meiler in 2012, I joined Annette Beck-Sickinger’s lab at Leipzig University to further study the neuropeptide Y4 receptor (Y4R). This particular trip is my fourth stay in Leipzig in the collaboration between the labs of Prof. Dr. Jens Meiler (Vanderbilt) and Prof. Dr. Annette Beck-Sickinger (Leipzig). This collaboration combines computational modeling with cell-based signaling and mutategensis assays to characterize the activation of Y4R and discover new compounds that may enhance Y4R signaling. Signaling through this receptor has been shown to be a potential avenue for treatment of obesity and related diseases such as diabetes.

Previous work with students in the Beck-Sickinger lab including Dr. Jan Stichel and Mario Schubert involving high-throughput screening and signaling assays led to the discovery of the first small-molecule modulators of the Y4 receptor. These compounds present varying behavior at Y4 and other, related, neuropeptide Y receptors, providing a good starting point for the design of highly specific small molecules that can “fine-tune” the behavior of this receptor with therapeutic potential.

This trip came at a turning-point in the Y4R project. With the completion of the first high-throughput screen and characterization of active compounds, I continued my work with Dr. Jan Stichel and Mario Schubert of the Beck-Sickinger lab, completing the scientific manuscript detailing the progress we made. This manuscript is currently under review for publication in a peer-reviewed journal. At the same time, we began applying computational modeling to characterize the interaction of Y4R and the compounds we discovered. During my stay in Leipzig, we reviewed computational models that propose potential compound-receptor binding modes. This information is valuable for understanding the structure and function of Y4R and may help with the design of more powerful and specific compounds.

During my stay, I presented this computational modeling work at the 11th International NPY-PYY-PP Meeting at Leipzig University with a poster titled “Discovery of novel small-molecule modulators of the human Y4 receptor” and received a scientific award for this poster. Lastly, I spent time completing my PhD thesis and necessary steps towards initiating thesis review.

As with all of my trips to Leipzig, I was fortunate to spend some time traveling and experiencing a bit of Germany’s culture and history. The conference provided an excellent schedule of experiences including a guided trip to the Leipzig zoo and a tour of the Porsche Leipzig factory. Especially impressive was the production floor and the fascinating picture of the organization and efficency necessary for such craftsmanship. I also spent a weekend in the city of Nuremberg (pictures 1-3) where I learned some of Germany’s midieval history, touring the beer cellars and enjoying music and food at the Volksfest.