title: Synthesis and biological activity of phosphonoacetate- and thiophosphonoacetate-modified 2'-O-methyl oligoribonucleotides.
abstract: Chimeric 2'-O-methyl oligoribonucleotides (2'-OMe ORNs) containing internucleotide linkages which were modified with phosphonoacetate (PACE) or thiophosphonoacetate (thioPACE) were prepared by solid-phase synthesis. The modified 2'-OMe ORNs contained a central phosphate or phosphorothioate sequence with up to 4 PACE or thioPACE modifications, respectively, at either end of the ORN in a "gapmer" motif. Both PACE and thioPACE 2'-OMe ORNs formed stable duplexes with complementary RNA. The majority of these duplexes had higher thermal melting temperatures than an unmodified RNA:RNA duplex. The modified 2'-OMe ORNs were effective passenger strands with complementary, unmodified siRNAs, for inducing siRNA activity in a dual luciferase assay in the presence of a lipid transfecting agent. As single strands, thioPACE 2'-OMe ORNs were efficiently taken up by HeLa cells in the absence of a lipid transfecting agent. Furthermore, thioPACE modifications greatly improved the potency of a 2'-OMe phosphorothioate ORN as an inhibitor of microRNA-122 in Huh7 cells, without lipid transfection.
authors: Department of Chemistry & Biochemistry, University of Colorado at Boulder, 215 UCB, Boulder, CO 80309-0215, USA.
authors: Richard N
authors: RN
authors: Threlfall
authors: Adrian G
authors: AG
authors: Torres
authors: Angelika
authors: A
authors: Krivenko
authors: Michael J
authors: MJ
authors: Gait
authors: Marvin H
authors: MH
authors: Caruthers
mesh_terms: D001483:Base Sequence; D002460:Cell Line; D006367:HeLa Cells; D006801:Humans; D035683:MicroRNAs / Q000037:antagonists & inhibitors; D009843:Oligoribonucleotides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D010746:Phosphonoacetic Acid / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D060327:Solid-Phase Synthesis Techniques; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D035683:MicroRNAs; D009843:Oligoribonucleotides; D034741:RNA, Small Interfering; D013438:Sulfhydryl Compounds; D010746:Phosphonoacetic Acid