Development of a selective high throughput screening assay for the discovery of compounds replacing frataxin in FA
Ataxia UK
University of Paris-Saclay
Friedreich’s ataxia (FA) is a neurodegenerative condition caused by defective expression of frataxin, a mitochondrial protein of elusive function. This group propose to explore new therapeutic approaches based on pharmacological replacement or enhancement of FXN function. They recently developed an assay which allows them to monitor the enzymatic activity of frataxin in vitro, which lead to better understanding of the role of frataxin. In this project, they plan use this biochemical assay to develop a cell-free high throughput screening assay of large chemical libraries for the identification of molecules mimicking or potentiating FXN activity. The main advantages of this assay compared to cell-based assays are to i) select molecules directly targeting the primary defect in FA, ii) circumvent cell-penetration, stability, toxicity and selectivity issues iii) reduce the time of screening to increase the number of conditions and compounds that could be tested. From this screen, they plan select a number of active compounds that will be further evaluated in animal models of FA, and modified by drug-design to improve their efficiency in vivo.
5.1 Pharmaceuticals