Discovery of Novel Longevity Therapeutics that Target Mitochondrial Enzymes
Researchers at CCM Biosciences, a New Jersey-based biopharmaceutical company, have reported the discovery of first-in-class compounds designed to restore the activity of SIRT3, a mitochondrial enzyme critical to cellular energy production and aging processes. Published in Physical Review X, this study introduces a novel mechanism of enzyme activation, bypassing the limitations of traditional allosteric modulation methods.
Efforts to develop therapeutics targeting the sirtuin family of enzymes, including SIRT3, have a long history, marked by both high expectations and significant setbacks. Over the past two decades, billions of dollars have been invested in sirtuin research, with notable examples including the $720 million acquisition of Sirtris Pharmaceuticals by GlaxoSmithKline in 2008 (quite a while ago). However, many early efforts faltered due to the limited scope of allosteric modulation, which only affects a small subset of proteins under specific conditions. Companies like Elysium Health shifted their focus away from targeted drug development toward nutraceutical approaches as a result.
SIRT3, often deemed undruggable due to its lack of an allosteric activation site, regulates mitochondrial function, which diminishes with age and is linked to conditions such as Alzheimer's, cardiovascular disease, and metabolic disorders. The compounds discovered by CCM Biosciences enhance SIRT3’s sensitivity to NAD+ (nicotinamide adenine dinucleotide), a cofactor whose levels decline with age. These compounds reportedly rejuvenate enzyme activity by optimizing the catalytic cycle of SIRT3, even in the context of depleted NAD+ levels.
Researchers at CCM Biosciences leveraged computational techniques, including quantum mechanics/molecular mechanics (QM/MM) simulations and deep learning algorithms, to identify novel interaction sites and design small molecules that enhance SIRT3’s function. By simulating the dynamic behavior of SIRT3 and its interaction with potential compounds, they pinpointed chemical scaffolds capable of stabilizing catalytic conformations and promoting enzymatic activity under conditions of NAD+ scarcity.
Structural alignment showing conformational changes in the SIRT3 loop region during the catalytic cycle: (a) Comparison of loop flexibility and α-helical structure between the SIRT3 ternary reactants complex (4FVT, pink), alkylimidate intermediate (4BVG, gray), and Honokiol-soaked complex (8V2N, blue). (b) Close-up highlighting differences between 4FVT and 8V2N, with Carba-NAD from 4FVT shown.
Dr. Michael Pollak, Professor of Medicine, Oncology, and Pharmacology at McGill University:
“Efforts have been underway for decades to activate signaling pathways regulated by sirtuins to combat age-related disorders, but prior efforts have encountered significant hurdles. 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.”
The therapeutic potential of these compounds extends to multiple age-related disorders, with preclinical studies in mice showing promising results in areas such as infertility. By addressing key limitations of previous approaches, CCM Biosciences’ drug candidates are ready for clinical trials in 2025. This development arrives amid a surge in investment in longevity research, which saw over $5 billion allocated in 2024 alone.
Topics: Novel Therapeutics
