Advanced Generation Multifunctional Radical Quenchers Advanced Generation Multifunctional Radical Quenchers The objectives of the proposed study involve the extension of a successful strategy to develop advanced generation drugs useful for treating Friedreichs ataxia by blunting mitochondrial degradation resulting from oxidative stress, and also augmenting ATP production. These drugs should be broadly applicable to the treatment of diseases involving mitochondrial electron transport chain (ETC) dysfunction. Specific Aims include: synthesis/evaluation of new types of CoQ analogues (MRQs; Multifunctional Radical Quenchers) capable of carrying out three functions catalytically in dysfunctional mitochondria, namely - oxidizing superoxide to oxygen - quenching lipid radicals resulting from oxidative stress - augmenting/restoring ATP production in FRDA cells study and optimization of lipophilic N-hydroxy-4-pyridones as MRQs study and optimization of alkylamino-coenzyme Q analogues as MRQs working with FARA and collaborators to evaluate the novel MRQs in cellular assay systems and animal models of FRDA With support from FARA, we have recently demonstrated that aza-analogues of coenzyme Q having stabilized semiquinone radical intermediates can catalytically and simultaneously quench superoxide and lipid peroxidation resulting from suboptimal mitochondrial function. Optimized analogues also restore ATP production in coenzyme Q-deficient lymphocytes, as well as cultured FRDA and LHON cells. We have prepared multigram quantities of our lead compound for studies in FRDA animal models, and are carrying out final structure optimization in this series to complete our work on this study. The purpose of the present initiative is the identification of advanced generation MRQs.
|Effective start/end date||8/1/12 → 10/30/13|
- Friedreich's Ataxia Research Alliance: $113,250.00
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