Site-specific conjugation of drug-like fragments to an antimiR scaffold as a strategy to target miRNAs inside RISC.
We synthesized a miR-122 antimiR library in which drug-like fragments were site-specifically introduced to short 2'-O-methyl-RNAs. At some sites selected fragments elevated cellular antimiR activity to that of an unmodified 23mer antimiR, whereas at others the same fragments abolished activity. The potency of the antimiRs correlated with uptake into miRISC.
Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zürich, 8093 Zürich, Switzerland. jonathan.hall@pharma.ethz.ch.
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Brunschweiger
Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zürich, 8093 Zürich, Switzerland. jonathan.hall@pharma.ethz.ch.
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Gebert
Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zürich, 8093 Zürich, Switzerland. jonathan.hall@pharma.ethz.ch.
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Lucic
Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zürich, 8093 Zürich, Switzerland. jonathan.hall@pharma.ethz.ch.
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Pradère
Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zürich, 8093 Zürich, Switzerland. jonathan.hall@pharma.ethz.ch.
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Jahns
Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zürich, 8093 Zürich, Switzerland. jonathan.hall@pharma.ethz.ch.
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Berk
Novartis Institutes for BioMedical Research, Global Discovery Chemistry, Novartis Campus, 4056 Basel, Switzerland.
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Hunziker
Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zürich, 8093 Zürich, Switzerland. jonathan.hall@pharma.ethz.ch.
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Hall
D001483:Base Sequence; D055808:Drug Discovery; D020868:Gene Silencing; D006801:Humans; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008958:Models, Molecular; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D020320:Oligoribonucleotides, Antisense / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D034743:RNA-Induced Silencing Complex / Q000378:metabolism*
C531907:MIRN122 microRNA, human; D035683:MicroRNAs; D020320:Oligoribonucleotides, Antisense; D034743:RNA-Induced Silencing Complex