title: 2'-fluoro-4'-thioarabino-modified oligonucleotides: conformational switches linked to siRNA activity.
abstract: The synthesis of oligonucleotides containing 2'-deoxy-2'-fluoro-4'-thioarabinonucleotides is described. 2'-Deoxy-2'-fluoro-5-methyl-4'-thioarabinouridine (4'S-FMAU) was incorporated into 18-mer antisense oligonucleotides (AONs). 4'S-FMAU adopts a predominantly northern sugar conformation. Oligonucleotides containing 4'S-FMAU, unlike those containing FMAU, were unable to elicit E. coli or human RNase H activity, thus corroborating the hypothesis that RNase H prefers duplexes containing oligonucleotides that can adopt eastern conformations in the antisense strand. The duplex structure and stability of these oligonucleotides was also investigated via circular dichroism (CD)- and UV- binding studies. Replacement of the 4'-oxygen by a sulfur atom resulted in a marked decrease in melting temperature of AON:RNA as well as AON:DNA duplexes. 2'-deoxy-2'-fluoro-4'-thioarabinouridine (4'S-FAU) was incorporated into 21-mer small interfering RNA (siRNA) and the resulting siRNA molecules were able to trigger RNA interference with good efficiency. Positional effects were explored, and synergy with 2'F-ANA, which has been previously established as a functional siRNA modification, was demonstrated.
authors.affiliation: Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, QC, Canada H3A 2K6.
authors.forename: Jonathan K
authors.initials: JK
authors.lastname: Watts
authors.forename: Niloufar
authors.initials: N
authors.lastname: Choubdar
authors.forename: Kashinath
authors.initials: K
authors.lastname: Sadalapure
authors.forename: Francis
authors.initials: F
authors.lastname: Robert
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Wahba
authors.forename: Jerry
authors.initials: J
authors.lastname: Pelletier
authors.forename: B Mario
authors.initials: BM
authors.lastname: Pinto
authors.forename: Masad J
authors.initials: MJ
authors.lastname: Damha
mesh_terms: D002236:Carbohydrate Conformation; D002942:Circular Dichroism; D009005:Monosaccharides / Q000737:chemistry*; D009705:Nucleosides / Q000138:chemical synthesis; D016376:Oligonucleotides, Antisense / Q000138:chemical synthesis / Q000737:chemistry*; D009943:Organophosphorus Compounds / Q000737:chemistry; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000737:chemistry*; D016914:Ribonuclease H / Q000378:metabolism; D014529:Uridine / Q000031:analogs & derivatives* / Q000737:chemistry
chemical_list: C512016:2'-fluoro-5-methyl-4'-thioarabinouridine; D009005:Monosaccharides; D009705:Nucleosides; D016376:Oligonucleotides, Antisense; D009943:Organophosphorus Compounds; D034741:RNA, Small Interfering; C434331:phosphoramidite; D016914:Ribonuclease H; D014529:Uridine