A team of UVM faculty are studying the structure, mechanism, and regulation of proteins that will help treat chronic pain and potentially offer a solution to the opioid crisis.
Under a five-year, near $2 million grant award from the National Institutes of Health (NIH), Assistant Professor Jianing Li as the principle investigator is working with her colleagues Professor Matthias Brewer of the Department of Chemistry and Professor Victor May of the College of Medicine to develop small-molecule medicines for stress-related diseases such as chronic pain and post-traumatic stress disorder. The goal is that these medicines would be effective for pain that is caused by stress, be non-addictive, and have potentially low side effects.
Specifically, the G protein-coupled pituitary adenylate cyclase-activating polypeptide receptor (PAC1R) is a new therapeutic target for endocrine, metabolic, and stress-related disorders. However, many questions regarding the protein structure and dynamics of PAC1R remain largely unanswered.
“The challenge of this protein is that no one knows what it looks like in three dimensions,” says Li. “We know the sequence of the PAC1R protein, and neuropeptide hormones that should fit into a pocket in PAC1R’s three-dimensional structure. We want to build the three-dimensional protein models with supercomputers, and design small molecules that will bind to the protein based on how the pocket looks like.”
The research, on the basis of structure-based drug design, will provide fundamental insights into protein structures, mechanisms, neuropeptide selectivity, and interactions with cellular signaling molecules. The researchers will employ state-of-the-art computational methods to model PAC1R structure and dynamics, with the goal of developing small molecules to modulate the protein function.
There are several classes of molecules that act differently on the PAC1R protein and affect various pathways in the brain. Some molecules can activate the protein and make it work, and some others may shut down the protein function, Li explains. It is difficult to accurately design the molecules and distinguish their roles without the protein models.
For their research, Li will model the PAC1R protein and design the molecules, Brewer will synthesize the molecules, and May will test the molecules in cells.
Treatments for Chronic Pain
Pain and stress-related disorder costs from healthcare and lost productivity have now exceeded those of cardiovascular disease, cancer, and diabetes. More than 65 million adults are affected by anxiety disorders alone in the United States and European Union, and healthcare costs in the U.S. exceed $42 billion a year.
The research has the potential to provide new approaches to treat disorders with few current therapeutic options. Li explains that chronic pain, for example, is typically treated with anti-inflammatory agents or opioids, and stress-related anxiety disorders are frequently treated with depressants and anti-psychotics. These clinical approaches often fail to offer relief to a large segment of the population or produce undesirable side effects.
Meanwhile, opioid treatments for chronic pain can lead to tolerance, addiction, or respiratory depression from μ-opioid receptor activation. Other migraine treatments have been ineffective or removed from clinical trials because of liver toxicity.
The collaborative effort between the three UVM faculty members goes back to 2015, when the trio were awarded a UVM REACH seed grant for the design, synthesis, and evaluation of small molecules to treat PTSD. They found a good compound to start with, and expand the project to target more stress-related diseases. However, more effort is still needed to improve the activity and selectivity.
That’s what they will work to improve with support of the NIH R01 grant.
“This protein we are working with is very promising because of its important role in regulating stress,” Li says. “In five years, we are expecting to find an active compound that selectively binds to the PAC1R protein and does not affect other similar ones or cause side effects.”