title: Anomeric inversion (from beta to alpha) in methylphosphonate oligonucleosides enhances their affinity for DNA and RNA.
abstract: Here we report that the poor binding of methylphosphonate oligodeoxynucleosides (MP-ODNs) to their nucleic acid targets can be improved by additional inversion of the anomeric configuration (from beta to alpha) in the sugar moieties to give a new class of analogs, MP alpha-oligonucleosides. MP alpha-dT12and MP 5' alpha-d(TCTTAACCCACA) 3' were synthesized and their ability to form hybrids with complementary single stranded (ss)DNA and ssRNA, as well as with double stranded (ds)DNA, was evaluated. The thermal stability of hybrids formed with MP alpha-analogs was compared with the affinity of phosphodiester (PO) and phosphorothioate (PS) beta- and alpha-oligomers for their targets. Non-ionic MP alpha-oligonucleosides bound to their complementary DNA and RNA strands more tightly than their homologues with natural beta-anomeric configuration did. With DNA target, MP alpha-oligomers formed duplexes more stable than the corresponding natural PO beta-oligomer did. MP alpha-heteropolymer hybridized to RNA target better than PS beta-oligonucleotide did but the hybrid was less stable (DeltaTm-0.5 degrees C per mod.) than the hybrid formed with the natural PO beta-oligomer. Only MP alpha-dT12 bound to dsDNA target at low salt concentration (0.1 M NaCl).
authors.affiliation: Laboratoire de Chimie Bio-organique, CC008, UMR 5625 CNRS-UM II, Université Montpellier II, Place Eugène Bataillon, 34095 Montpellier Cedex 5, France. debart@univ-montp2.fr
authors.forename: F
authors.initials: F
authors.lastname: Debart
authors.forename: A
authors.initials: A
authors.lastname: Meyer
authors.forename: J J
authors.initials: JJ
authors.lastname: Vasseur
authors.forename: B
authors.initials: B
authors.lastname: Rayner
mesh_terms: D001665:Binding Sites; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000378:metabolism*; D018076:DNA, Complementary / Q000378:metabolism; D004277:DNA, Single-Stranded / Q000378:metabolism*; D009690:Nucleic Acid Conformation; D009693:Nucleic Acid Hybridization / Q000187:drug effects; D009838:Oligodeoxyribonucleotides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000737:chemistry* / Q000378:metabolism; D011061:Poly A / Q000378:metabolism; D011071:Poly T / Q000378:metabolism; D012313:RNA / Q000378:metabolism*; D018075:RNA, Complementary / Q000378:metabolism; D012965:Sodium Chloride / Q000494:pharmacology; D013696:Temperature; D013816:Thermodynamics
chemical_list: D018076:DNA, Complementary; D004277:DNA, Single-Stranded; D009838:Oligodeoxyribonucleotides; D009943:Organophosphorus Compounds; D018075:RNA, Complementary; D011061:Poly A; D011071:Poly T; C015465:poly(dA); C032627:methylphosphonic acid; D012965:Sodium Chloride; D012313:RNA; D004247:DNA