Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 81, Issue -, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2023.117208
Keywords
Pyrrole-imidazole polyamide (PIP); Repeat expansion disease; Friedreich ?s ataxia (FRDA); Therapeutic gene modulation
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A compound was synthesized to increase the transcription of the FXN gene in cells from FRDA patients at a lower concentration than previously reported. However, high concentrations of the compound are toxic, but toxicity can be reduced with a host-guest complex.
GAA repeat expansion in the first intron of the frataxin (FXN) gene represses the transcription of FXN, and that induces Friedreich's ataxia (FRDA). Pyrrole-imidazole polyamides (PIPs) are the class of oligopeptide that targets double-stranded DNA with sequence selectivity. Previously, bromodomain inhibitors such as JQ1 conjugated with PIPs were reported to selectively increase transcription. Here, we report the synthesis of a compound that increases the transcription of FXN in cells derived from an FRDA patient. The compound was effective in lower (one tenth) concentration than the compound that previously reported. High concentration of the compound is toxic, but toxicity was reduced with a host-guest complex.
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