The University of Southampton
University of Southampton Institutional Repository

Next-generation peptide nucleic acid chimeras exhibit high affinity and potent gene silencing

Next-generation peptide nucleic acid chimeras exhibit high affinity and potent gene silencing
Next-generation peptide nucleic acid chimeras exhibit high affinity and potent gene silencing

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.

0006-2960
582-589
Debacker, Alexandre J.
3ccf0314-9a35-4129-a3c3-c60a909973da
Sharma, Vivek K.
b1eae149-9db0-49de-8159-c58d8cfda375
Meda Krishnamurthy, Pranathi
3ad8e1e2-39f5-48f9-ae62-2156ffdb2bc6
O'Reilly, Daniel
9d098ea6-4ac4-44ab-b440-e0d8be3734a5
Greenhill, Rachel
86503556-f987-42ec-a489-4b709355e476
Watts, Jonathan K.
c4de85ee-aaa3-4e7d-99b3-147a4de4f01c
Debacker, Alexandre J.
3ccf0314-9a35-4129-a3c3-c60a909973da
Sharma, Vivek K.
b1eae149-9db0-49de-8159-c58d8cfda375
Meda Krishnamurthy, Pranathi
3ad8e1e2-39f5-48f9-ae62-2156ffdb2bc6
O'Reilly, Daniel
9d098ea6-4ac4-44ab-b440-e0d8be3734a5
Greenhill, Rachel
86503556-f987-42ec-a489-4b709355e476
Watts, Jonathan K.
c4de85ee-aaa3-4e7d-99b3-147a4de4f01c

Debacker, Alexandre J., Sharma, Vivek K., Meda Krishnamurthy, Pranathi, O'Reilly, Daniel, Greenhill, Rachel and Watts, Jonathan K. (2019) Next-generation peptide nucleic acid chimeras exhibit high affinity and potent gene silencing. Biochemistry, 58 (6), 582-589. (doi:10.1021/acs.biochem.8b00827).

Record type: Article

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.

Full text not available from this repository.

More information

e-pub ahead of print date: 6 December 2018
Published date: 12 February 2019

Identifiers

Local EPrints ID: 428956
URI: https://eprints.soton.ac.uk/id/eprint/428956
ISSN: 0006-2960
PURE UUID: 6f62a372-5138-4540-8bd9-be979fde89f6

Catalogue record

Date deposited: 15 Mar 2019 17:30
Last modified: 15 Mar 2019 17:30

Export record

Altmetrics

Contributors

Author: Alexandre J. Debacker
Author: Vivek K. Sharma
Author: Pranathi Meda Krishnamurthy
Author: Daniel O'Reilly
Author: Rachel Greenhill
Author: Jonathan K. Watts

University divisions

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of https://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×