Selective binding of pyrido[2,3-d]pyrimidine 2'-deoxyribonucleoside to AT base pairs in antiparallel triple helices.
Triple helix-forming oligonucleotides (TFOs) offer the potential to specifically modulate expression of gene in a sequence dependent manner. TFOs containing G and T residues that bind to duplex DNA, forming a series of GGC and TAT base triplets, have been well studied. It has been observed that T is relatively nonspecific in that it binds with similar affinity to AT, GC, and CG base pairs. This may significantly reduce the specificity of a given TFO, leading to undesired effects on the expression of genes unrelated to the intended target. We have now prepared 3-(2-deoxy-beta-D-erythro-pentofuranosyl)-pyrido[2,3-d]pyrimidine-2,7(8H )- dione (P) and incorporated it into TFOs using the solid-support, phosphoramidite chemistry. It has been demonstrated that a limited substitution of P for T in a G-rich 26-mer TFO can improve binding specificity for AT base pairs in antiparallel motif under certain conditions. The specificity exhibited by P is suggestive of base pair specific interactions that influence the binding strength and consequently enhance the potential therapeutic application of TFOs. However, the effect of substitution of P for T is dependent on the binding conditions, as well as the number of position of substitutions.
Durland
R H
RH
Triplex Pharmaceutical Corporation, The Woodlands, Texas 77380, USA.
Rao
T S
TS
Jayaraman
K
K
Revankar
G R
GR
D000225:Adenine / Q000378:metabolism*; D001482:Base Composition; D001483:Base Sequence; D001665:Binding Sites; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D011725:Pyridines / Q000737:chemistry / Q000378:metabolism*; D011741:Pyrimidine Nucleosides / Q000737:chemistry / Q000378:metabolism*; D013941:Thymine / Q000378:metabolism*
C095038:3-(2-deoxypentofuranosyl)pyrido(2,3-d)pyrimidine-2,7(8H)-dione; D011725:Pyridines; D011741:Pyrimidine Nucleosides; D000225:Adenine; D013941:Thymine