Abstract
The 6-aminoglucosamine ring of the aminoglycoside antibiotic neomycin B (ring II) was conjugated to a 16-mer peptide nucleic acid (PNA) targeting HIV-1 TAR RNA. For this purpose, we prepared the aminoglucosamine monomer 15 and attached it to the protected PNA prior to its cleavage from the solid support. We found that the resulting PNA-aminoglucosamine conjugate is stable under acidic conditions, efficiently taken up by the human cells and fairly distributed in both cytosol and nucleus without endosomal entrapment because cotreatment with endosome-disrupting agent had no effect on its cellular distribution. The conjugate displayed very high target specificity in vitro and strongly inhibited Tat mediated transactivation of HIV-1 LTR transcription in a cell culture system. The unique properties of this new class of PNA conjugate suggest it to be a potential candidate for therapeutic application.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylglucosamine / analogs & derivatives
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Acetylglucosamine / chemical synthesis
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Acetylglucosamine / pharmacokinetics*
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Anti-HIV Agents / chemical synthesis
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Anti-HIV Agents / chemistry
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Anti-HIV Agents / pharmacokinetics*
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Antiviral Agents / chemistry
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Binding Sites / genetics
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Biological Availability
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Cell Line, Tumor
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Cell Nucleus / drug effects
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Cell Nucleus / metabolism
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Cell Nucleus / ultrastructure
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Cytosol / drug effects
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Cytosol / metabolism
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Cytosol / ultrastructure
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Endosomes / drug effects
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Endosomes / metabolism
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Endosomes / ultrastructure
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Fluorescein-5-isothiocyanate / chemistry
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Framycetin / analogs & derivatives*
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Genome, Viral / drug effects
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HIV Long Terminal Repeat / drug effects
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HIV Long Terminal Repeat / genetics
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HIV-1 / drug effects*
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HIV-1 / genetics
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Humans
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Peptide Nucleic Acids / chemistry
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Peptide Nucleic Acids / pharmacokinetics*
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Peptide Nucleic Acids / pharmacology
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RNA, Viral / antagonists & inhibitors
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RNA, Viral / genetics
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Response Elements / drug effects
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Spectrometry, Fluorescence
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Transcription, Genetic / drug effects
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Transcriptional Activation / drug effects*
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tat Gene Products, Human Immunodeficiency Virus / antagonists & inhibitors*
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tat Gene Products, Human Immunodeficiency Virus / genetics
Substances
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Anti-HIV Agents
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Antiviral Agents
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Peptide Nucleic Acids
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RNA, Viral
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tat Gene Products, Human Immunodeficiency Virus
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Framycetin
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Fluorescein-5-isothiocyanate
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Acetylglucosamine