Synergistic effect of phosphorothioate, 5'-vinylphosphonate and GalNAc modifications for enhancing activity of synthetic siRNA

Bioorg Med Chem Lett. 2016 Jun 15;26(12):2817-2820. doi: 10.1016/j.bmcl.2016.04.063. Epub 2016 Apr 27.

Abstract

Chemical modifications are essential to improve metabolic stability and pharmacokinetic properties of siRNA to enable their systemic delivery. We investigated the effect of combing the phosphorothioate (PS) modification with metabolically stable phosphate analog (E)-5'-vinylphosphonate and GalNAc cluster conjugation on the activity of fully 2'-modified siRNA in cell culture and mice. Our data suggest that integrating multiple chemical approaches in one siRNA molecule improved potency 5-10 fold and provide a roadmap for developing more efficient siRNA drugs.

Keywords: 3′-GalNAc cluster; 5′-Vinylphosphonate siRNA; Alternating F/OMe siRNA; Fully modified siRNA; siRNA phosphorothioates.

MeSH terms

  • Acetylgalactosamine / chemistry
  • Acetylgalactosamine / metabolism*
  • Animals
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • HeLa Cells
  • Humans
  • Liver / drug effects
  • Liver / metabolism
  • Mice
  • Mice, Transgenic
  • Molecular Structure
  • Organophosphonates / chemistry
  • Organophosphonates / metabolism*
  • PTEN Phosphohydrolase / antagonists & inhibitors*
  • PTEN Phosphohydrolase / metabolism
  • Phosphates / chemistry
  • Phosphates / metabolism*
  • RNA, Small Interfering / metabolism
  • RNA, Small Interfering / pharmacology*
  • Structure-Activity Relationship
  • Vinyl Compounds / chemistry
  • Vinyl Compounds / metabolism*

Substances

  • Organophosphonates
  • Phosphates
  • RNA, Small Interfering
  • Vinyl Compounds
  • vinylphosphonic acid
  • PTEN Phosphohydrolase
  • Pten protein, mouse
  • Acetylgalactosamine
  • thiophosphoric acid