Familial dysautonomia is a debilitating congenital neurodegenerative disorder with no causative therapy. It is caused by a homozygous mutation in ELP1 gene, resulting in the production of the transcript lacking exon 20. The compounds studied as potential treatments include the clinical candidate kinetin, a plant hormone from the cytokinin family. We explored the relationship between the structure of a set of kinetin derivatives (N = 72) and their ability to correct aberrant splicing of the ELP1 gene. Active compounds can be obtained by the substitution of the purine ring with chlorine and fluorine at the C2 atom, with a small alkyl group at the N7 atom, or with diverse groups at the C8 atom. On the other hand, a substitution at the N3 or N9 atoms resulted in a loss of activity. We successfully tested a hypothesis inspired by the remarkable tolerance of the position C8 to substitution, postulating that the imidazole of the purine moiety is not required for the activity. We also evaluated the activity of phytohormones from other families, but none of them corrected ELP1 mRNA aberrant splicing. A panel of in vitro ADME assays, including evaluation of transport across model barriers, stability in plasma and in the presence of liver microsomal fraction as well as plasma protein binding, was used for an initial estimation of the potential bioavailability of the active compounds. Finally, a RNA-seq data suggest that 8-aminokinetin modulates expression spliceosome components.

Department of Chemical Biology Faculty of Science Palacký University Šlechtitelů 27 CZ 78371 Olomouc Czech Republic

Institute of Molecular and Translational Medicine Faculty of Medicine and Dentistry Palacký University Hněvotínská 3 775 15 Olomouc Czech Republic

Isotope Laboratory Institute of Experimental Botany Academy of Sciences of the Czech Republic Vídeňská 1083 142 00 Prague 4 Czech Republic

Laboratory of Experimental Biology Faculty of Science Palacký University Šlechtitelů 27 CZ 78371 Olomouc Czech Republic

Laboratory of Growth Regulators Institute of Experimental Botany AS CR and Palacký University Šlechtitelů 27 CZ 78371 Olomouc Czech Republic

University of Natural Resources and Life Sciences Vienna Department of Biotechnology Institute of Computational Biology Vienna Austria

Citace poskytuje Crossref.org