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Long-time medicinal chemists Jay Parrish and Gabriel Martinez have developed small molecules that target mitochondrial DNA depletion, aiming to fix energy-related diseases. Their team at Pretzel Therapeutics discovered a compound named PZL-A, which activates the POLγ enzyme responsible for copying mitochondrial DNA. This enzyme is vital because errors or mutations in it can lead to serious conditions like mitochondrial DNA depletion syndromes (MDDS), affecting energy production in muscles, the brain, and other organs.
The research, published in Nature, used a screen of 270,000 compounds to find activators for POLγ. PZL-A was able to fix mutant versions of this enzyme in patient cells, increasing mitochondrial DNA, oxygen use, and ATP output. The molecule works by binding inside the enzyme structure and helping it make longer, more accurate DNA strands. The scientists showed this effect in both skin cells and lab-grown brain cells from patients.
Though PZL-A itself won’t be used in treatment, it has helped create a related drug, PX578, which has already entered Phase 1 clinical trials in healthy adults. PX578 is taken once daily and can enter the brain, making it useful for nervous system diseases. Unlike gene therapy, these small molecules can work throughout the body and don’t require expensive delivery methods.
Pretzel Therapeutics chose this chemical approach because gene editing can't yet reach mitochondria effectively. Their small molecules work across many tissues and don’t need to target specific mutations, which makes them cheaper and more practical. This broad reach is important for conditions like MDDS, which affect multiple organs.
The company plans to first treat rare genetic disorders and then move toward conditions like Parkinson’s and age-related muscle loss. Meanwhile, Parrish and Martinez say they are also exploring ways to improve energy use in cells by shifting from ATP to fat burning, with possible applications in obesity treatment.
Parrish says they’re only beginning this journey but hopes the research can lead to better treatments for aging and neurodegeneration in the future.
