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Biochemistry. 2018 Dec 6. doi: 10.1021/acs.biochem.8b00827. [Epub ahead of print]

Next-generation PNA chimeras exhibit high affinity and potent gene silencing.

Abstract

We present a new design of mixed-backbone antisense oligonucleotides (ASOs) containing both DNA and peptide nucleic acid (PNA). Previous generations of PNA-DNA chimeras showed low binding affinity, reducing their potential as therapeutics. The addition of a 5'-wing of locked nucleic acid as well as the combination of modified nucleotide and PNA monomer at the junction between PNA and DNA gave high affinity to the chimeras. The resulting ASOs demonstrated high serum stability and elicited robust RNase H-mediated cleavage of complementary RNA. These properties allowed the chimeric ASOs to demonstrate high gene silencing efficacy and potency in cells, comparable with LNA gapmer ASOs, both by lipid transfection and gymnosis.

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