Single strand targeted triplex-formation. Destabilization of guanine quadruplex structures by foldback triplex-forming oligonucleotides.
Oligonucleotides that can hybridize to single-stranded complementary polypurine nucleic acid targets by Watson-Crick base pairing as well as by Hoogsteen base pairing, referred to here as foldback triplex-forming oligonucleotides (FTFOs), have been designed. These oligonucleotides hybridize with target nucleic acid sequences with greater affinity than antisense oligonucleotides, which hybridize to the target sequence only by Watson-Crick hydrogen bonding [Kandimalla, E. R. and Agrawal, S. Gene(1994) 149, 115-121 and references cited therein]. FTFOs have been studied for their ability to destabilize quadruplexes formation by RNA or DNA target sequences. The influence of various DNA/RNA compositions of FTFOs on their ability to destabilize RNA and DNA quadruplexes has been examined. The ability of the FTFOs to destabilize quadruplex structures is related to the structurally and thermodynamically stable foldback triplex formed between the FTFO and its target sequence. Antisense oligonucleotides (DNA or RNA) that can form only a Watson-Crick double helix with the target sequence are unable to destabilize quadruplex structures of RNA and DNA target sequences and are therefore limited in their repertoire of target sequences. The quadruplex destabilization ability of FTFOs is dependent on the nature of the cation present in solution. The RNA quadruplex destabilization ability of FTFOs is -20% higher in the presence of sodium ion than potassium ion. The use of FTFOs, which can destabilize quadruplex structure, opens up new areas for development of oligonucleotide-based therapeutics, specifically, targeting guanine-rich sequences that exist at the ends of pro- and eukaryotic chromosomes and dimerization regions of retroviral RNA.
Kandimalla
E R
ER
Hybridon, Inc., Worcester, MA 01605, USA.
Agrawal
S
S
D001483:Base Sequence; D004247:DNA / Q000737:chemistry*; D016373:DNA, Antisense / Q000737:chemistry; D054856:G-Quadruplexes; D015750:Genes, gag / Q000235:genetics; D006147:Guanine / Q000502:physiology; D015497:HIV-1 / Q000235:genetics; D006863:Hydrogen-Ion Concentration; D008745:Methylation; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D009838:Oligodeoxyribonucleotides / Q000138:chemical synthesis / Q000737:chemistry* / Q000302:isolation & purification; D011188:Potassium / Q000737:chemistry; D012313:RNA / Q000737:chemistry*; D016372:RNA, Antisense / Q000737:chemistry; D012964:Sodium / Q000737:chemistry
D016373:DNA, Antisense; D009838:Oligodeoxyribonucleotides; D016372:RNA, Antisense; C051802:triplex DNA; D006147:Guanine; D012313:RNA; D004247:DNA; D012964:Sodium; D011188:Potassium