The researchers will present their results today at the spring meeting of the American Chemical Society (ACS). ACS Spring 2024 is a hybrid meeting being held virtually and in person March 17-21; it features nearly 12,000 presentations on a range of science topics.
“We cannot replace exercise; exercise is important on all levels,” says Bahaa Elgendy, the project’s principal investigator who is presenting the work at the meeting. “If I can exercise, I should go ahead and get the physical activity. But there are so many cases in which a substitute is needed.”
Exercise benefits both mind and body. In this case, Elgendy, a professor of anesthesiology at Washington University School of Medicine in St. Louis, and his colleagues are hoping to recapitulate its potent physical effects — namely, exercise’s ability to enhance muscle cells’ metabolism and growth, along with improved muscle performance.
A drug that can mimic these effects could offset the muscle atrophy and weakness that can occur as people age or are affected by cancer, certain genetic conditions or other reasons they are unable to carry out regular physical activity. It could also potentially counter the effects of other drugs, such as new weight-loss medications that cause the loss of both fat and muscle, according to Elgendy.
The metabolic changes associated with exercise kick off with the activation of specialized proteins, known as estrogen-related receptors (ERRs), which come in three forms: ERRα, ERRβ and ERRγ. After about a decade of work, Elgendy and his colleagues developed a compound named SLU-PP-332, which activates all three forms, including the most challenging target, ERRα. This type of ERR regulates exercise-induced stress adaptation and other important physiological processes in muscle. In experiments with mice, the team found this compound increased a fatigue-resistant type of muscle fiber while also improving the animals’ endurance when they ran on a rodent treadmill.
To identify SLU-PP-332, the researchers scrutinized the structure of the ERRs and how they bind to molecules that activate them. Then, to improve upon their discovery and develop variations that could be patented, Elgendy and his team designed new molecules to strengthen the interaction with the receptors and thus provoke a stronger response than what SLU-PP-332 can provide. When developing the new compounds, the team also optimized the molecules for other desirable characteristics, such as stability and low potential for toxicity.
The team compared the potency of SLU-PP-332 with that of the new compounds by looking at RNA, a measure of gene expression, from about 15,000 genes in cells from rat heart muscle. The new compounds prompted a greater increase in the presence of the RNA, suggesting they more potently simulate the effects of exercise.
Research using SLU-PP-332 suggests targeting ERRs could be useful against specific diseases. Studies in animals with this preliminary compound indicate that it could have a benefit against obesity, heart failure or a decline in kidney function with age. The results in the updated research suggest the new compounds could have similar effects.
ERR activity also appears to counter damaging processes that occur in the brain in patients diagnosed with Alzheimer’s disease and those who have other neurodegenerative conditions. While SLU-PP-332 cannot pass into the brain, some of the new compounds were developed to do so.
“In all of these conditions, ERRs play a major role,” Elgendy says. “If you have a compound that can activate them effectively, you could generate so many beneficial effects.”
Elgendy and his colleagues hope to test the new compounds in animal models through Pelagos Pharmaceuticals, a startup company they have co-founded. They are also looking into the possibility of developing the compounds as potential treatments for neurodegenerative disorders.
The research was supported by the National Institute on Aging of the National Institutes of Health under Award Numbers R21AG065657 and RF1AG077160.
Visit the ACS Spring 2024 program to learn more about this presentation, “Exercise in a pill: Design and synthesis of novel ERR agonists as exercise mimetics,” and more scientific presentations.
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Title
Exercise in a pill: Design and synthesis of novel ERR agonists as exercise mimetics
Abstract
Estrogen-related receptors (ERRs) belong to the nuclear hormone receptor superfamily, a group of ligand-activated transcription factors. Ligands for nuclear receptors have the ability to either activate or inhibit the transcription factors responsible for regulating numerous genes associated with vital physiological functions, including metabolism, immunity, inflammation, homeostasis, development, cellular growth, and reproduction. Within the estrogen-related receptors subfamily, there exist three members: ERRα, ERRβ, and ERRγ. These receptors are closely related to estrogen receptors (ERs); however, ERRs exhibit constitutive activity unlike ER receptors, and can function without ligands. ERRα is known to be highly intractable as a drug target. We recently developed the first class of ERR pan agonists that was shown to induce ERRα-specific acute aerobic exercise genetic program. ERRα activation was critical for enhancing exercise endurance in mice, and our chemical tool increased mitochondrial function and cellular respiration in a skeletal muscle cell line. Using state-of-the-art computational techniques and iterative medicinal chemistry, we have identified novel chemotypes of potent ERR pan agonists with improved drug-like and pharmacokinetic properties for future use in animal models.
The progress we made in developing pan agonists that target all three isoforms of ERR is predicted to launch this target's clinical translatability. Anticipated applications for these novel ligands extend beyond their role as exercise mimetics. They hold significant potential for treating metabolic disorders, conditions linked to mitochondrial dysfunction, as well as neurodegenerative diseases.
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