Effect of 2'-O-[2-[2-(N,N-dimethylamino)ethoxy]ethyl] modification on activity of gapmer antisense oligonucleotides containing 2',4'-constrained 2'-O-ethyl nucleic acid

Bioorg Med Chem Lett. 2015 Apr 15;25(8):1688-1691. doi: 10.1016/j.bmcl.2015.03.004. Epub 2015 Mar 7.

Abstract

We evaluated the effect of combining 2'-O-[2-[2-(N,N-dimethylamino)ethoxy]ethyl] (2'-O-DMAEOE), a 2'-cationic modification, with a 2',4'-constrained 2'-O-ethyl nucleic acid (cEt BNA) on the activity of an antisense oligonucleotide (ASO) using PTEN as a model target. Our results suggest that replacing one cEt BNA nucleotide with 2'-O-DMAEOE nucleotide at the 5'-end of a 2-10-2 gapmer ASO maintained the potency relative to parent ASO in liver. The cationic 2'-O-DMAEOE modification did not improve the activity of ASO in extra-hepatic tissues. Results from this study provide guidance to design improved antisense oligonucleotide drugs.

Keywords: Antisense; Cationic modification; DMAEOE; Oligonucleotide; cEt BNA.

MeSH terms

  • Animals
  • Cell Line
  • Ethane / analogs & derivatives*
  • Ethane / chemistry
  • Ethers / chemistry*
  • Liver / metabolism
  • Mice
  • Nucleic Acids / chemistry*
  • Oligonucleotides, Antisense / chemistry*
  • Oligonucleotides, Antisense / metabolism
  • PTEN Phosphohydrolase / genetics
  • PTEN Phosphohydrolase / metabolism
  • Phosphates / chemistry
  • RNA, Messenger / chemistry
  • RNA, Messenger / metabolism
  • Transition Temperature

Substances

  • 2'-O-(2-(2-(N,N-dimethylamino)ethoxy)ethyl)
  • Ethers
  • Nucleic Acids
  • Oligonucleotides, Antisense
  • Phosphates
  • RNA, Messenger
  • phosphorodithioic acid
  • PTEN Phosphohydrolase
  • Ethane