Synthesis and biological evaluation of sialyl-oligonucleotide conjugates targeting leukocyte B trans-membranal receptor CD22 as delivery agents for nucleic acid drugs

Bioorg Med Chem. 2016 Jun 1;24(11):2397-2409. doi: 10.1016/j.bmc.2016.03.047. Epub 2016 Mar 29.

Abstract

Antisense oligonucleotides (ASOs) modified with ligands which target cell surface receptors have the potential to significantly improve potency in the target tissue. This has recently been demonstrated using triantennary N-acetyl d-galactosamine conjugated ASOs. CD22 is a cell surface receptor expressed exclusively on B cells thus presenting an attractive target for B cell specific delivery of drugs. Herein, we reported the synthesis of monovalent and trivalent ASO conjugates with biphenylcarbonyl (BPC) modified sialic acids and their study as ASO delivery agents into B cells. CD22 positive cells exhibited reduced potency when treated with ligand modified ASOs and mechanistic examination suggested reduced uptake into cells potentially as a result of sequestration of ASO by other cell-surface proteins.

Keywords: Antisense; CD22; Conjugation; Multivalency; Sialosides.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • B-Lymphocytes / drug effects*
  • Dose-Response Relationship, Drug
  • Drug Delivery Systems*
  • Humans
  • Molecular Structure
  • Nucleic Acids / metabolism*
  • Oligonucleotides / chemical synthesis
  • Oligonucleotides / chemistry
  • Oligonucleotides / pharmacology*
  • Sialic Acid Binding Ig-like Lectin 2 / antagonists & inhibitors*
  • Sialic Acids / chemical synthesis
  • Sialic Acids / chemistry
  • Sialic Acids / pharmacology*
  • Structure-Activity Relationship

Substances

  • CD22 protein, human
  • Nucleic Acids
  • Oligonucleotides
  • Sialic Acid Binding Ig-like Lectin 2
  • Sialic Acids