Next-Generation Peptide Nucleic Acid 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 a modified nucleotide and a PNA monomer at the junction between PNA and DNA yielded high-affinity 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 those of LNA gapmer ASOs, via both lipid transfection and gymnosis.

journal_name

Biochemistry

journal_title

Biochemistry

authors

Debacker AJ,Sharma VK,Meda Krishnamurthy P,O'Reilly D,Greenhill R,Watts JK

doi

10.1021/acs.biochem.8b00827

subject

Has Abstract

pub_date

2019-02-12 00:00:00

pages

582-589

issue

6

eissn

0006-2960

issn

1520-4995

journal_volume

58

pub_type

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