title: Structural characterization and biological evaluation of small interfering RNAs containing cyclohexenyl nucleosides.
abstract: CeNA is an oligonucleotide where the (deoxy)ribose sugars have been replaced by cyclohexenyl moieties. We have determined the NMR structure of a CeNA:RNA duplex and have modeled this duplex in the crystal structure of a PIWI protein. An N puckering of the ribose nucleosides, a 2H3 conformation of the cyclohexenyl nucleosides, and an A-like helix conformation of the backbone, which deviates from the standard A-type helix by a larger twist and a smaller slide, are observed. The model of the CeNA:RNA duplex bound to the PIWI protein does not show major differences in the interaction of the guide CeNA with the protein when compared with dsRNA, suggesting that CeNA modified oligonucleotides might be useful as siRNAs. Incorporation of one or two CeNA units in the sense or antisense strands of dsRNA led to similar or enhanced activity compared to unmodified siRNAs. This was tested by targeting inhibition of expression of the MDR1 gene with accompanying changes in P-glycoprotein expression, drug transport, and drug resistance.
authors.affiliation: Laboratory of Medicinal Chemistry, Rega Institute for Medical Research, Minderbroedersstraat 10, Leuven, Belgium.
authors.forename: Koen
authors.initials: K
authors.lastname: Nauwelaerts
authors.forename: Michael
authors.initials: M
authors.lastname: Fisher
authors.forename: Matheus
authors.initials: M
authors.lastname: Froeyen
authors.forename: Eveline
authors.initials: E
authors.lastname: Lescrinier
authors.forename: Arthur Van
authors.initials: AV
authors.lastname: Aerschot
authors.forename: Dong
authors.initials: D
authors.lastname: Xu
authors.forename: Robert
authors.initials: R
authors.lastname: DeLong
authors.forename: Hyumin
authors.initials: H
authors.lastname: Kang
authors.forename: Rudolph L
authors.initials: RL
authors.lastname: Juliano
authors.forename: Piet
authors.initials: P
authors.lastname: Herdewijn
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D001483:Base Sequence; D003510:Cyclohexanes / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D009690:Nucleic Acid Conformation; D009705:Nucleosides / Q000737:chemistry* / Q000378:metabolism; D009841:Oligonucleotides / Q000737:chemistry / Q000378:metabolism; D012330:RNA, Double-Stranded / Q000737:chemistry* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003510:Cyclohexanes; D009705:Nucleosides; D009841:Oligonucleotides; D012330:RNA, Double-Stranded; D034741:RNA, Small Interfering