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• W2065946475 startingPage "9329" @default.
• W2065946475 abstract "Unlocked nucleic acid (UNA) is an acyclic analogue of RNA that can be introduced into RNA or DNA oligonucleotides. The increased flexibility conferred by the acyclic structure fundamentally affects the strength of base pairing, creating opportunities for improved applications and new insights into molecular recognition. Here we test how UNA substitutions affect allele-selective inhibition of expression of trinucleotide repeat genes Huntingtin (HTT) and Ataxin-3 (ATX-3). We find that the either the combination of mismatched bases and UNA substitutions or UNA substitutions alone can improve potency and selectivity. Inhibition is potent, and selectivities of >40-fold for inhibiting mutant versus wild-type expression can be achieved. Surprisingly, even though UNA preserves the potential for complete base pairing, the introduction of UNA substitutions at central positions within fully complementary duplexes leads to >19-fold selectivity. Like mismatched bases, the introduction of central UNA bases disrupts the potential for cleavage of substrate by argonaute 2 (AGO2) during gene silencing. UNA-substituted duplexes are as effective as other strategies for allele-selective silencing of trinucleotide repeat disease genes. Modulation of AGO2 activity by the introduction of UNA substitutions demonstrates that backbone flexibility is as important as base pairing for catalysis of fully complementary duplex substrates. UNA can be used to tailor RNA silencing for optimal properties and allele-selective action." @default.
• W2065946475 created "2016-06-24" @default.
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• W2065946475 date "2013-11-27" @default.
• W2065946475 modified "2023-09-23" @default.
• W2065946475 title "Allele-Selective Inhibition of Expression of Huntingtin and Ataxin-3 by RNA Duplexes Containing Unlocked Nucleic Acid Substitutions" @default.
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• W2065946475 doi "https://doi.org/10.1021/bi4014209" @default.
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• W2065946475 hasPublicationYear "2013" @default.
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