Auburn researcher targets receptors for new therapies
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Kristine Griffett has your headache in mind. And those aching joints. Even your high cholesterol.
That’s because Griffett, an assistant professor of pharmacology in the department of anatomy, physiology, and pharmacology at Auburn University College of Veterinary Medicine, is hard at work developing new compounds that will target receptors in the body and could a day lead to new, less addictive drug therapies for inflammation, pain, chronic hypercholesterolemia and cardio-metabolic problems such as obesity, diabetes and atherosclerosis.
To achieve this goal, Griffett is studying compounds that target nuclear receptors, proteins naturally present in the body, bind to DNA and control the activities of genes involved in metabolism, inflammation, pain, cancer and many other aspects of physiology. Humans have 48 of these receptors, each with a distinct role in physiology and disease.
“Most people don’t realize the therapeutic relevance of these receptors,” Griffett explained. “But about 30% of prescription drugs on the market today target them. For example, corticosteroids target the glucocorticoid receptor and contraceptives target estrogen or progesterone receptors.
For Griffett, however, the focus is on receptors that have been less commonly studied. She is testing new compounds designed and synthesized by her collaborators to activate these receptors, first at the cellular level, then, if the compound seems promising, in mice. At this stage, the efficacy of the compounds is also tested against current therapeutics already on the market. “Typically,” noted Griffett, “about one in three of the promising compounds identified in these early tests will eventually become ‘lead’ compounds that could eventually be patented, licensed, and further evaluated in clinical trials.”
“My research focuses mainly on less characterized receptors as therapeutic targets,” she added. “This allows me to study how receptors function under normal physiological conditions, as well as work with medicinal chemists to design synthetic compounds to determine their effectiveness in activating these receptors for the treatment of various diseases.”
One of its receptor targets is designated REV-ERB. It is involved in processes as diverse as maintaining circadian rhythms, reducing inflammation, and regulating lipids and glucose in the body, but Griffett is primarily interested in the analgesic role of REV-ERB. “In humans and animals,” she said, “chronic low-grade inflammation is a key factor in the development of chronic pain. When we activate this receptor, we see a significant reduction in inflammation and “normal” sensitivity to external stimuli.
“This suggests that REV-ERB activation may reduce inflammation and have an analgesic effect,” she continued. “This is particularly exciting because it provides a non-opioid pathway for pain treatment, with little to no risk of addiction. The REV-ERB project has just received funding notice from the National Institutes of Neurological Disorders and strokes and is currently in its early stages.
In addition to REV-ERB, Griffett is also evaluating compounds that target hepatic receptors, or LXRs, which may hold the key to treating familial hypercholesterolemia, or FH, an inherited genetic disorder that raises LDL cholesterol levels, cardiovascular problems and premature death. . In the United States, HF is estimated to affect about one in 200 people, but many cases go undiagnosed and untreated. Other related diseases, such as dyslipidemia, which causes lipid imbalance, and atherosclerosis, a condition that develops due to plaque buildup in the arteries, can also be treated with some of these compounds.
“I am currently working with Pelagos Pharma on international patents and rights to several compounds that target liver X receptors (LXRs) for the treatment of familial hypercholesterolemia, dyslipidemia and atherosclerosis,” Griffett said. “I recently identified an LXR target gene in the intestine called steryl-o-acyltransferase 2 (Soat2), which is an identified clinical target for atherosclerosis. When Soat2 expression is high, a person is at higher risk of developing atherosclerosis.
“I worked to make an LXR compound that can be taken orally and is only active in the gut,” she continued. “In fact, it causes the mice to excrete cholesterol in their feces rather than reabsorb it, and it has no effect on other tissues. This work not only identified Soat2 as a target of LXR, but also identified tissue-selective drugs that have potential in the treatment of atherosclerosis.We plan to complete the preclinical phase in about a year, and then we will try to obtain funds for clinical trials on the treatment of atherosclerosis. HF.
In addition to ongoing work with REV-ERB and LXR, targeting other nuclear receptors is a much more promising area, not only for better treatments to help control diseases such as pain and high cholesterol, but also to improve therapies for a variety of other diseases and conditions.
“My work is very dynamic,” Griffett concluded, “because these receptors are involved in many different physiological processes. That’s what makes it fun and sometimes frustrating! The goal is to develop new compounds and therapeutics, but we will also learn a lot about how these receptors work along the way.
The research reported in this publication was supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under award number R01NS126204. The content is the sole responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.