title: Hoechst 33258 selectively inhibits group I intron self-splicing by affecting RNA folding.
abstract: Fungal pathogens are increasing in prevalence due to an increase in resistant strains and the number of immunocompromised humans. Candida albicans is one of these pathogens, and approximately 40% of strains contain a group I self-splicing intron, which is a potential RNA drug target, in their large subunit rRNA precursor. Here, we report that Hoechst 33258 and derivatives thereof are selective inhibitors of C. albicans group I intron self-splicing with an IC50 of 17 microM in 2 mM Mg2+. Chemical probing of the intron in the presence of Hoechst 33258 reveals that the folding of several nucleotides in the P4/P6 region of the intron is affected. A nucleotide near the J4/5 region is protected from chemical modification in the presence of Hoechst 33258 and several nearby are more reactive; this suggests that this region is the molecule's binding site. These results expand the available information on small-molecule targeting of RNA and suggest that the RNA-targeting scaffold provided by Hoechst may prove valuable in designing compounds that inhibit the functions of RNA.
authors.affiliation: Department of Chemistry, University of Rochester, Rochester, NY 14627-0216, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Disney
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Childs
authors.forename: Douglas H
authors.initials: DH
authors.lastname: Turner
mesh_terms: D001483:Base Sequence; D006690:Bisbenzimidazole / Q000494:pharmacology*; D002176:Candida albicans / Q000235:genetics*; D020134:Catalytic Domain / Q000235:genetics; D020128:Inhibitory Concentration 50; D007438:Introns / Q000235:genetics*; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D012326:RNA Splicing / Q000187:drug effects* / Q000235:genetics; D044563:RNA, Ribosomal, Self-Splicing / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D044563:RNA, Ribosomal, Self-Splicing; D006690:Bisbenzimidazole