Exercise in a pill: New compound mimics the physical boost of exercise

Researchers have developed compounds that mimic the benefits of exercise in rodent cells, potentially offering new treatments for muscle atrophy and diseases such as heart failure and Alzheimer’s.

New compounds that mimic the effects of exercise could treat muscle atrophy and neurodegenerative diseases, with promising research results presented at ACS Spring 2024.

Doctors have long prescribed exercise to improve and protect health. In the future, a pill may offer some of the same benefits as exercise. Now, researchers report on new compounds that appear to be able to mimic the physical boost of exercise, at least inside rodent cells. This discovery could lead to a new way to treat muscle atrophy and other medical conditions in people, such as heart failure and neurodegenerative diseases.

Presentation of results at ACS Spring 2024

The researchers presented their results at the spring meeting of the American Chemical Society (ACS). ACS Spring 2024 is a hybrid meeting held virtually and in person from March 17 to 21; includes nearly 12,000 presentations on a variety of scientific topics.

“We cannot replace exercise; Exercise is important at all levels,” says Bahaa Elgendy, principal investigator of the project presenting the work at the meeting. “If I can exercise, I should go ahead and do physical activity. But there are many cases where a replacement is needed.”


Bahaa Elgendy understands that some people may be too busy or too lazy to exercise. So his team is looking to mimic the benefits of exercise using a pill. The new therapeutics could also help people facing muscle loss due to disease or aging.

Potential of the drug that mimics exercise

Exercise benefits the mind as well as the body. In this case, Elgendy, a professor of anesthesiology at the Washington University School of Medicine in St. Louis, and his colleagues hope to recapitulate its powerful physical effects, namely the ability of exercise to improve metabolism and muscle cell growth, along with muscle improvement. performance

A drug that could mimic these effects could offset muscle atrophy and weakness that can occur as people age or are affected by cancer, certain genetic conditions or other reasons that make them unable to perform regular physical activity. It could also counteract the effects of other drugs, such as new weight-loss drugs that cause the loss of both fat and muscle, according to Elgendy.

Development of the compound SLU-PP-332

The metabolic changes associated with exercise are initiated by the activation of specialized proteins known as estrogen-related receptors (ERRs), which come in three forms: ERRα, ERRβ, and ERRγ. After a decade of work, Elgendy and his colleagues developed a compound called SLU-PP-332, which activates all three forms, including the most difficult target, ERRα. This type of ERR regulates adaptation to exercise-induced stress and other important physiological processes in muscle. In experiments with mice, the team found that this compound increased a type of fatigue-resistant muscle fiber while improving the animals’ endurance when they ran on a treadmill with rodents.

To identify SLU-PP-332, the researchers examined the structure of ERRs and how they bind to the molecules that activate them. Then, to improve 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 elicit a stronger response than what SLU-PP-332 can provide. In developing the new compounds, the team also optimized the molecules for other desirable characteristics, such as stability and low toxicity potential.

Research and future applications

The team compared the potency of SLU-PP-332 with that of the new compounds by looking RNA, a measure of gene expression, from about 15,000 genes in rat heart muscle cells. The new compounds caused a greater increase in the presence of the RNA, suggesting that they more strongly mimic the effects of exercise.

Research using SLU-PP-332 suggests that targeting ERRs could be useful against specific diseases. Animal studies with this preliminary compound indicate that it might have a benefit against obesity, heart failure, or age-related decline in kidney function. The results of the updated research suggest that the new compounds could have similar effects.

ERR activity also appears to counteract harmful processes occurring in the brain in diagnosed patients Alzheimer’s disease and those with other neurodegenerative conditions. Although SLU-PP-332 cannot get into the brain, some of the new compounds were developed to do so.

“In all these conditions, ERRs play an important role,” says Elgendy. “If you have a compound that can effectively activate them, you could generate so many beneficial effects.”

Elgendy and his colleagues hope to test the new compounds in animal models through Pelagos Pharmaceuticals, a start-up company they co-founded. They are also studying the possibility of developing the compounds as potential treatments for neurodegenerative disorders.

title
Exercise in a pill: design and synthesis of novel ERR agonists as exercise mimetics

Summary
Estrogen-related receptors (ERRs) belong to the nuclear hormone receptor superfamily, a group of ligand-activated transcription factors. Nuclear receptor ligands have the ability to activate or inhibit transcription factors responsible for regulating numerous genes associated with vital physiological functions, such as metabolism, immunity, inflammation, homeostasis, development, cell growth. cellular and reproduction. Within the estrogen-related receptor subfamily, there are three members: ERRα, ERRβ, and ERRγ. These receptors are closely related to estrogen receptors (ER); however, ERRs exhibit constitutive activity unlike ER receptors, and can function without ligands. ERRα is known to be very intractable as a drug target. We have recently developed the first class of pan ERR agonists shown to induce an acute aerobic exercise genetic program specific for ERRα. ERRα activation was critical for improving 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 pan ERR agonists with improved pharmacokinetic and drug-like properties for future use in animal models.

It is anticipated that the progress we have made in developing pan agonists that target all three ERR isoforms will launch the clinical translatability of this goal. The intended applications for these new ligands extend beyond their role as exercise mimetics. They have significant potential to treat metabolic disorders, conditions related to mitochondrial dysfunction, as well as neurodegenerative diseases.

The research was supported by the National Institute on Aging National Institutes of Health under award numbers R21AG065657 and RF1AG077160.


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