Nobel prize winner from Duke connects with colleagues at UNC to study cell receptorsApril 12, 2016
Editor's note: This is the first article in a series exploring four Duke-UNC collaborations funded in 2016 through the Clinical and Translational Science Awards (CTSAs) at Duke and UNC.
As health conditions go, allergies, hypertension, and ulcers wouldn’t seem to have a lot in common. But many of the drugs used to treat these and other conditions work in a surprisingly similar way: by fitting together like lock and key with one of about 1,000 proteins found woven at the surface of our cells, known as G protein-coupled receptors (GPCR for short).
About 30 percent of all FDA-approved drugs in use today work by turning particular GPCRs on or off, making this class of receptors the most common of all drug targets.
"This collaboration builds on long-standing strengths in both labs. Our chances of success are very, very high.”
-- Robert Lefkowitz, MD, PhD
But GPCR experts Robert Lefkowitz, MD, Professor of Medicine at Duke School of Medicine, and Bryan Roth, MD, PhD, Professor of Pharmacology at UNC School of Medicine, think there’s still plenty of unrealized potential for drugs aimed at GPCRs. With funding support from the NIH Clinical and Translational Science Awards (CTSAs) Program at Duke and UNC-Chapel Hill, the Lefkowitz and Roth labs have teamed up to develop a new approach to understanding much more precisely how particular chemical compounds influence GPCR signals. The ultimate goal is to make fundamental discoveries that yield the next-generation of GPCR-targeted drugs.
“These receptors are major drug targets,” said Bryan Roth, MD, PhD, Professor of Pharmacology at UNC School of Medicine. “Our hope is that we’ll gain new understanding through this collaboration to accelerate the search for better and more effective treatments.”
“It’s always good to have inter-institutional collaboration like this,” Lefkowitz said. “Dr. Roth and I are friends and colleagues. We know each other well and this collaboration builds on long-standing strengths in both labs. Our chances of success are very, very high.”
A Brief History
Lefkowitz discovered the GPCR superfamily of receptors back in the 1970s. His lab has been busy working on the tools to understand them ever since. He received the Nobel Prize in Chemistry in 2012 for his efforts, along with Brian Kobilka of Stanford University School of Medicine, a former postdoc in his lab.
As Lefkowitz explains it, when a chemical messenger like adrenaline or dopamine binds a GPCR with great specificity, the receptor is “unlocked,” stimulating a change inside the cell. When adrenaline binds an adrenergic receptor, for example, the heart starts beating harder. If a beta-blocker binds to the receptor in place of adrenaline, it interrupts the process. The heart doesn’t have to work so hard.
Researchers know that the receptors work by stimulating G proteins (hence the name), which amplify the signal. More recently, Lefkowitz and his colleagues found something they hadn’t expected despite all the earlier years of study: certain chemical messengers (also known as “ligands”) activate GPCRs selectively to produce different downstream signals.
This finding means that scientists’ view of GPCR signals is woefully incomplete. And, if those gaps can be filled, it might open the door to more precise and safer GPCR-targeted treatments.
“This was a tremendous insight in terms of drug development because it meant that now you could try to develop drugs which might be more specific and selective than anything we had before,” Lefkowitz said. “Now, they might not only react with one particular receptor, but they could [also] activate that receptor to do only some of the things it normally does while perhaps blocking others.”
Measuring the Bias
Lefkowitz launched a company in 2007 to pursue the discovery and development of “biased ligands” targeting GPCRs. The company, called Trevena, already has two drugs in advanced clinical trials, one for pain and the other for heart failure. But to fully realize the therapeutic potential of drugs based on this concept, they needed a streamlined method to measure GPCR signals across all possible pathways. (Humans have about 1,000 different GPCRs operating through 19 different proteins.)
Lefkowitz’s and Roth’s new collaboration aims to develop and validate a platform enabling them to define complete signaling profiles of GPCR-targeted molecules for the first time, taking advantage of Lefkowitz’s expertise in measuring GPCR binding and Roth’s expertise and resources in drug screening. The ultimate goal is to use this platform to develop detailed “signatures” of GPCR-targeted drug activity, both to better understand existing drugs and to develop new and better ones.
Their platform works by fusing a GPCR of interest to each of the 19 possible signal-transducing proteins. A state-of-the-art liquid-handling robot at UNC, which Roth uses in his work with the NIH-funded Psychoactive Drug Screening Program, makes light work of the testing. The robot can test 96 samples at a time, meticulously diluting drugs or other compounds to just the right concentrations before the fusion proteins are added. By measuring changes in the binding affinity of an endogenous ligand, such as a hormone, or a drug to each of those 19 fusion proteins, the researchers can get a more thorough understanding of how the signal or drug works in a test tube, without laborious tests on cells.
“We’re able to profile these signals across all possible pathways with incredibly high throughput,” said Ryan Strachan, an Assistant Research Professor at UNC and instrumental member of the collaborative team. “You can just imagine how many cell assays you’d have to do. It would really be impossible and then compounded by the fact that you still wouldn’t know what you were really measuring in a cell. Here, we’ve experimentally isolated specific signaling pathways—that’s the real advance.”
Strachan says he and Biswaranjan Pani, a post-doc in Lefkowitz’s lab, will share the work, focusing their attention first on receptors for adrenaline, dopamine, and angiotensin. Those receptors and the transducer proteins they signal through are already well known and studied, Strachan says, but “we’re blowing this wide open by looking at them all because no one looks at them all.”
The new team of Lefkowitz and Roth is one of four to receive collaborative grants from the Duke CTSA and the CTSA at UNC-Chapel Hill this year. These DTRI Duke/UNC Collaborative Pilot Program awards are part of an effort to promote inter-institutional collaborations that can turn basic scientific discoveries into advances in patient care.
UNC and Duke are both members of the Clinical and Translational Awards (CTSA) Program, a national consortium created to improve the way biomedical research is conducted across the country. The CTSA program is funded by the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
By Kendall K. Morgan