CCM Biosciences Scientists Discover First-in-Class Longevity Therapeutics

Novel therapeutics rejuvenate a previously undruggable mitochondrial regulator of aging through a new mode of enzyme activation

MOUNT LAUREL, N.J., Jan. 9, 2025 /PRNewswire/ -- Applying a newly identified biophysical mechanism of enzyme activation, researchers at the longevity therapeutics division of the diversified biopharmaceutical company CCM Biosciences, Inc., have discovered and characterized first-in-class enzyme activators for a previously undruggable master regulator of cellular energy production. These first-in-class compounds fully restore the enzyme's activity to youthful levels and hold significant potential for clinical development to address a range of age-related disorders, including Alzheimer's, Parkinson's, cardiovascular conditions, and metabolic diseases.

Finding enzyme-activating compounds has historically been challenging because they typically rely on a mechanism called allosteric modulation, which is feasible in less than 10% of proteins. Recently, researchers at CCM Biosciences and its affiliated R&D center Chakrabarti Advanced Technology expanded the scope of enzyme activation beyond allosteric modulation by introducing novel physical principles for enzyme activation. Using these principles, they applied computational and experimental design techniques to identify compounds that drastically enhance the activity of the previously undruggable enzyme Sirtuin-3 (SIRT3), which is centrally involved in regulating human aging. This study was published in Physical Review X, the flagship journal of the American Physical Society (APS), on 22 October 2024.

Notably, SIRT3, the major mitochondrial sirtuin enzyme, plays a critical role in determining health span and lifespan through its regulation of mitochondria—the cellular powerhouses that decline with age. However, SIRT3 was long considered undruggable due to the absence of a known allosteric site. The lead compounds discovered by CCM scientists work by significantly increasing SIRT3's sensitivity to NAD+ (nicotinamide adenine dinucleotide), an essential metabolic cofactor that decreases with age and contributes to the onset of many age-related diseases.

Remarkably, CCM's compounds fully restored SIRT3 activity under NAD+ depletion conditions mimicking old age, with NAD+ levels reduced by half. The scientists demonstrated this effect across multiple cell lines used in aging studies. These compounds are also undergoing animal testing in mice for age-related disorders, including infertility, where they have outperformed both NAD+ supplements and existing sirtuin activators.

"Our compounds restore SIRT3 function to youthful levels and offer a novel approach to addressing the molecular hallmarks of aging," said Dr. Thomas Delacroix, a senior author involved in the study.

Dr. Michael Pollak, Professor of Medicine, Oncology and Pharmacology at McGill University and an expert on clinical trials for age-related disorders and the biochemistry of sirtuin-regulated signaling pathways, says that "The discoveries by CCM Biosciences pertaining to the design of drug candidates that can activate the major mitochondrial pathways regulated by sirtuins, along with the clinical development plan for evaluation of efficacy as well as safety of these drug candidates, revitalize this area of drug development."

Reference
Title of original paper: Computationally Driven Discovery and Characterization of SIRT3-Activating Compounds that Fully Recover Catalytic Activity under NAD⁺ Depletion

Journal: Physical Review X

DOI: 10.1103/PhysRevX.14.041019

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