title: 8-Oxoguanosine switches modulate the activity of alkylated siRNAs by controlling steric effects in the major versus minor grooves.
abstract: Small interfering double-stranded RNAs have been synthesized bearing one or more base modifications at nucleotide positions 4, 11, and/or 16 in the guide strand. The chemically modified base is an N(2)-alkyl-8-oxo-7,8-dihydroguanine (alkyl = propyl, benzyl) that can alternatively pair in a Watson-Crick sense opposite cytosine (C) or as a Hoogsteen pair opposite adenine (A). Cellular delivery with C opposite led to effective targeting of A-containing but not C-containing mRNA sequences in a dual luciferase assay with RNA interference levels that were generally as good as or better than unmodified sequences. The higher activity is ascribed to an inhibitory effect of the alkyl group projecting into the minor groove of double-stranded RNA preventing off-target binding to proteins such as PKR (RNA-activated protein kinase).
authors: Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, Utah 84112-0850, USA.
authors: Arunkumar
authors: A
authors: Kannan
authors: Erik
authors: E
authors: Fostvedt
authors: Peter A
authors: PA
authors: Beal
authors: Cynthia J
authors: CJ
authors: Burrows
mesh_terms: D000478:Alkylation; D001483:Base Sequence; D006151:Guanosine / Q000031:analogs & derivatives* / Q000737:chemistry; D011485:Protein Binding; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000737:chemistry*; D019892:eIF-2 Kinase / Q000737:chemistry / Q000378:metabolism
chemical_list: D034741:RNA, Small Interfering; D006151:Guanosine; C046215:8-hydroxyguanosine; D019892:eIF-2 Kinase