Scripps Research Institute awarded grant to design assays for exploring potential target for obesity, Type 2 diabetes

Expanded funding could help validate novel therapeutic target

The Scripps Research Institute has been awarded a $1.3 million grant by the National Institutes of Health (NIH) to develop a series of tests at its Florida campus to help explore the potential of a protein that has emerged as a highly attractive target for the treatment of obesity and Type 2 diabetes.

Patricia McDonald, an associate scientific director in the Translational Research Institute at Scripps Florida and an assistant professor in the Department of Molecular Therapeutics, is the principal investigator for the three-year project funded by the NIH's National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

"Because obesity and diabetes are two of the most serious health problems facing us, the need for novel treatments has never been greater," McDonald said. "Some recent studies in animal models have shown that activating the G protein-coupled receptor GPR119 improves glucose homeostasis or balance, while positively affecting both food intake and weight gain. This funding will help us design new assays that will explore the overall potential of GPR119 - and may one day lead to more effective treatments."

G protein-coupled receptors (GPCRs) are the largest and most diverse protein family in the human genome. They transduce or convert extracellular stimuli including neurotransmitters, light, hormones, lipids, and peptides into intracellular signals through a number of signaling pathways. Approximately one third, and perhaps as many as half, of currently marketed drugs are designed to target these receptors.

GPR119 is expressed predominantly in the pancreas and gut of humans and rodents and in the rat brain. When activated, the receptor promotes secretion of a specific hormone, called Glucagon-Like Peptide-1 (GLP-1), in the intestines, which in turn increases insulin secretion from the pancreas; both are key components in regulating the balance of glucose in the body. Although some modulators of GPR119 have been discovered, they do not necessarily mimic the receptor's natural ligand and have thus turned out to be mostly unsuitable for use in studying the receptor's biology and function.

"In terms of treating metabolic disease through modulation of GPCRs," McDonald said, "an obvious candidate such as the GLP-1 receptor has been a historically difficult target to track with small molecules, but GPR119 is much more amenable to modulation, plus it also regulates the GLP-1 axis, which is what makes it such a potentially valuable target in diabetes and obesity. We chose this particular receptor for those reasons - and the fact that it's being studied extensively by the pharmaceutical industry."

McDonald hopes that once the new assays are developed, and molecular probes created, the process will lead to the identification of small molecule compounds that can be used therapeutically. The probes themselves might even have potential in this regard.

"We'll be studying these probes to see if they have any drug-like properties, particularly if they show any significant activity against the GPR119 receptor," she said. "The obvious goal would be to improve a probe's therapeutic qualities - oral bioavailability, for example - while keeping its high level of activity, a process that can be a lot more difficult than it sounds."

Expanding Knowledge in the Field

With the human genome sequenced, science now has a good handle on just how many GPCRs exist - at least 1,000 or more. Of those, McDonald said, scientists have a good understanding of what approximately 200 of them actually do and what activates them; another 600 or so are involved in taste and smell. The remaining receptors are known as orphan receptors, whose function and natural ligands have yet to be discovered (also a receptor class that the McDonald lab is actively pursuing).

"We want to look at developing assay environments that are more physiologically relevant to the disease state in question," she said, "to make them more akin to what's really going on in the whole animal. We hope that the in vitro pharmacology that we uncover in GPR119 will help bridge the gap between the limits of cell-based assays and in vivo studies. That's why this funding is so important to eventually find more effective treatments for diabetes and obesity."

In her work, McDonald collaborates with the medicinal chemists at Scripps Florida.

"When small molecule candidates demonstrate some sort of efficacy in our cell-based assays, we work very closely with the chemists to improve their efficacy," she said. "The chemists modify these molecules and then they cycle back to the biologists and our assays for further evaluation. It's a very symbiotic relationship."