Mitochondria Nucleotides Targeting – MINUTAR

mtDNA depletion syndrome (MDS) is a group of mitochondrial disorders characterized by a reduced mtDNA copy number which occurr in early childhood and for which no curative therapy is yet available. Depletion of mtDNA result from mutations in nuclear genes especially involved in the regulation of mitochondrial deoxyribonucleotides (dNTP) pool. In this context, the discovery of new drugs allowing efficient and targeted delivery of nucleotides to mitochondria is of great interest in the focus of a new treatment strategies in MDS. Our project proposes the development of an original approach combining prodrug and mitochondria-targeted nucleotides strategies. A first screening of model compounds was performed in induced pluripotent stem cell (iPSC)-based cultures modelling MDS disease. Thus, promising compounds able to restore ATP production in mitochondria have been identified. In addition, mitochondria-targeted prodrugs of nucleoside and nucleotide derivatives have been synthesized and studied by fluorescence microscopy experiments. Among them, two compounds were indeed able to localized in mitochondria. Our main objective is now to combine these two structural moieties (targeting vector and pronucleotide) in a single compound and to study their in vitro and in vivo potential in order to validate our proof of concept. In addition, stability in various media, toxicity and their impact on the main mitochondrial functions will be determined for the best compounds.