Synthesis and biological evaluation of sialyl-oligonucleotide conjugates targeting leukocyte B trans-membranal receptor CD22 as delivery agents for nucleic acid drugs.
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.
Department of Chemistry, Université de Montréal, PO Box 6128, Succ., Centre-ville, Montréal, Québec H3C 3J7, Canada.
Gabrielle
G
St-Pierre
Department of Chemistry, Université de Montréal, PO Box 6128, Succ., Centre-ville, Montréal, Québec H3C 3J7, Canada.
Sudip
S
Pal
Medicinal Chemistry, Ionis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, United States.
Michael E
ME
Østergaard
Medicinal Chemistry, Ionis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, United States.
Tianyuan
T
Zhou
Medicinal Chemistry, Ionis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, United States.
Jinghua
J
Yu
Medicinal Chemistry, Ionis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, United States.
Michael
M
Tanowitz
Medicinal Chemistry, Ionis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, United States. Electronic address: pseth@ionisph.com.
Punit P
PP
Seth
Department of Chemistry, Université de Montréal, PO Box 6128, Succ., Centre-ville, Montréal, Québec H3C 3J7, Canada. Electronic address: Stephen.Hanessian@umontreal.ca.
Stephen
S
Hanessian
D001402:B-Lymphocytes / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D006801:Humans; D015394:Molecular Structure; D009696:Nucleic Acids / Q000378:metabolism*; D009841:Oligonucleotides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000037:antagonists & inhibitors*; D012794:Sialic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
C497867:CD22 protein, human; D009696:Nucleic Acids; D009841:Oligonucleotides; D051918:Sialic Acid Binding Ig-like Lectin 2; D012794:Sialic Acids
Antisense; CD22; Conjugation; Multivalency; Sialosides