Estrogen-Related Receptor Agonists as Exercise Mimetic Drugs

Just as the research community is interested in finding pharmaceutical ways to provoke some the beneficial reactions to calorie restriction, there is also considerable effort devoted to the search for drug candidates that can mimic some of the benefits of exercise. If the history of calorie restriction mimetic drug development is any guide, this will be a slow process, and the resulting compounds will produce lesser benefits than actual exercise, as they will only touch on a small subset of the processes involved. Still, there is no shortage of programs in this space, and here is one example.

Exercise benefits both mind and body. 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. 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, researchers 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, the team designed new molecules to strengthen the interaction with the receptors and thus provoke a stronger response than 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. 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.



Would simply raising estrogen levels have same effect?

Posted by: John at March 25th, 2024 11:45 AM
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