Abstract
A convenient method for the synthesis of several triantennary GalNAc clusters based on a nitromethanetrispropionic acid core was developed. The synthetic approach involves pentafluorophenolic ester intermediates which can be used in a one-pot, seven reaction procedure to quickly prepare a variety of triantennary GalNAc conjugated ASOs. The GalNAc clusters were conjugated to the 5'-end of an antisense oligonucleotide and evaluated for activity in primary mouse hepatocytes where they showed ∼10-fold improvement in activity.
Keywords:
Conjugate; GalNAc; Nucleic acid; Synthesis.
Copyright © 2016 Elsevier Ltd. All rights reserved.
MeSH terms
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Acetylgalactosamine / analogs & derivatives*
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Acetylgalactosamine / chemical synthesis*
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Acetylgalactosamine / pharmacology
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Animals
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Hepatocytes / drug effects
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Hepatocytes / metabolism
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Indicators and Reagents
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Mice
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Nitro Compounds / chemical synthesis*
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Nitro Compounds / pharmacology
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Oligonucleotides, Antisense / chemical synthesis*
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Oligonucleotides, Antisense / pharmacology
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Propionates / chemical synthesis*
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Propionates / pharmacology
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Scavenger Receptors, Class B / metabolism
Substances
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Indicators and Reagents
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Nitro Compounds
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Oligonucleotides, Antisense
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Propionates
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Scarb1 protein, mouse
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Scavenger Receptors, Class B
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nitromethanetrispropionic acid
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Acetylgalactosamine