Improved hybridisation potential of oligonucleotides comprising O-methylated anhydrohexitol nucleoside congeners

Nucleic Acids Res. 2001 Oct 15;29(20):4187-94. doi: 10.1093/nar/29.20.4187.

Abstract

The hybridising potential of anhydrohexitol nucleoside analogues (HNAs) is well documented, but tedious synthesis of the monomers hampers their development. In a search for better analogues, the synthesis of two new methylated anhydrohexitol congeners 1 and 2 was accomplished and the physico-chemical properties of their respective oligomers were evaluated. Generally, oligonucleotides (ONs) containing the 3'-O-methyl derivative 1 showed a small increase in thermal stability towards complementary sequences as compared to HNA. Compared to the altritol modification, 3'-O-methylation seems to cause a small decrease in thermal stability of duplexes, especially when targeting RNA. These results suggest the possibility of derivatisation of the 3'-hydroxyl group of altritol-containing congeners without significantly affecting the thermal stability of the duplexes. The methyl glycosidic analogues 2 likewise increased the affinity for RNA in comparison with well-known HNA, while at the same time being economically more favorable monomers. However, homopolymers of 2 displayed self-pairing, but not so homopolymers of 1. Upon incorporation of the hexitols within RNA sequences in an effort to induce a beneficial pre-organised structure, the positive effect of the 3'-O-methyl derivative 1 proved larger than that of 2.

Publication types

  • Evaluation Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Methylation
  • Nucleic Acid Hybridization / methods*
  • Oligonucleotides, Antisense / chemical synthesis
  • Oligonucleotides, Antisense / chemistry*
  • Oligonucleotides, Antisense / metabolism*
  • Polyribonucleotides / metabolism
  • RNA / metabolism
  • RNA Stability
  • Sugar Alcohols / metabolism*

Substances

  • Oligonucleotides, Antisense
  • Polyribonucleotides
  • Sugar Alcohols
  • altritol
  • RNA