Discovery of drug candidates for the Barth syndrome using a yeast-based screening approach and higher eurkaryotic models of this disease
Deborah Tribouillard-Tanvier, PhD, Permanent Researcher, CNRS, University of Bordeaux, Bordeaux, France

Award: US $44,000 over 2-year period

*Funding for this award was provided by Association Barth France

Abstract:

Using libraries of FDA-approved chemical compounds, we isolated 21 drugs that substantially improve respiratory growth of CL-remodeling deficient (taz1∆) yeast. 8-10 of these compounds will be tested for their capacity to rescue also mitochondrial function in various human and mice cellular models of Barth syndrome (BTHS). Those drugs that provide the best results will be tested directly in a knock-out TAZ1 mice. Some of the selected compounds are well-known inhibitors of cytosolic protein synthesis. We demonstrated that a slight modulation of this cellular activity is sufficient to fully restore oxidative phosphorylation in taz1∆yeast. This is an important finding that shed new light on the pathogenesis of BTHS. We propose to determine the mechanism by which a partial inhibition of cytosolic protein synthesis compensates for a lack in CL-remodeling, both in yeast and mammalian cells. Finally, we propose to investigate the mechanism of action of the other studied drug candidates using a variety of approaches to identify the cellular pathways and components they target. Our project will provide a number of novel findings about the pathogenesis of BTHS and help for future development of potential therapeutic pathways against this disease.