An Investigation of Mild Mitochondrial Uncouplers and Their Potential to Treat Obesity
- Publication Type:
- Thesis
- Issue Date:
- 2025
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Mitochondrial uncoupling by small molecule protonophores is a promising therapeutic strategy for the treatment of several diseases including obesity; however, the toxicity associated with uncoupling complicates their progress towards clinical applications. A possible solution is the development of mild uncouplers that partially depolarise mitochondria without affecting ATP production. In this study, a series of aryl amide-substituted fatty acid protonophores were synthesised and demonstrated that appropriate aromatic substitution patterns produce mild uncoupling. Using a vesicle-based proton transport assay, it was uncovered that maximum rate of transmembrane proton transport is an integral factor distinguishing between mild and full uncoupling. This was attributed to a diminished capacity of some arylamides’ ability to form membrane permeable dimers in the rate limiting step of the protonophoric cycle. To expand on this, a library of more “drug-like” aryl amides with shortened alkyl chains were developed with the goal of developing a mild uncoupler with optimal oral bioavailability. From this library, one aryl amide analogue was studied in mice models with high fat diet induced-obesity. Overall, this provides the first experimental evidence linking mild mitochondrial uncoupling to proton transport rate, and that proton transport rate of the aryl amides can be manipulated by substitution pattern and lipophilicity.
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