Anomeric inversion (from β to α) 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 β to α) in the sugar moieties to give a new class of analogs, MP α-oligonucleosides. MP α-dT12 and MP 5' α-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 α-analogs was compared with the affinity of phosphodiester (PO) and phosphorothioate (PS) β- and α-oligomers for their targets. Non-ionic MP α-oligonucleosides bound to their complementary DNA and RNA strands more tightly than their homologues with natural β-anomeric configuration did. With DNA target, MP α-oligomers formed duplexes more stable than the corresponding natural PO β-oligomer did. MP α-heteropolymer hybridized to RNA target better than PS β-oligonucleotide did but the hybrid was less stable (ΔT(m) -0.5°C per mod.) than the hybrid formed with the natural PO β-oligomer. Only MP α-dT12 bound to dsDNA target at low salt concentration (0.1 M NaCl).