Correction of aberrant splicing of ELP1 pre-mRNA by kinetin derivatives - A structure activity relationship study
Jazyk angličtina Země Francie Médium print-electronic
Typ dokumentu časopisecké články
PubMed
39756144
DOI
10.1016/j.ejmech.2024.117176
PII: S0223-5234(24)01058-4
Knihovny.cz E-zdroje
- Klíčová slova
- ADME in vitro, Alternative splicing, Cytokinin, ELP1, Kinetin, mRNA metabolism,
- MeSH
- kinetin * farmakologie chemie MeSH
- lidé MeSH
- molekulární struktura MeSH
- prekurzory RNA * genetika metabolismus MeSH
- sestřih RNA * účinky léků MeSH
- transkripční elongační faktory metabolismus genetika MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- Elp1 protein, human MeSH Prohlížeč
- kinetin * MeSH
- prekurzory RNA * MeSH
- transkripční elongační faktory MeSH
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.
Citace poskytuje Crossref.org
