Peptide-LNA oligonucleotide conjugates

I Kira Astakhova, Lykke Haastrup Hansen, Birte Vester, Jesper Wengel

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

Although peptide-oligonucleotide conjugates (POCs) are well-known for nucleic acids delivery and therapy, reports on internal attachment of peptides to oligonucleotides are limited in number. To develop a convenient route for preparation of internally labeled POCs with improved biomedical properties, peptides were introduced into oligonucleotides via a 2'-alkyne-2'-amino-LNA scaffold. Derivatives of methionine- and leucine-enkephalins were chosen as model peptides of mixed amino acid content, which were singly and doubly incorporated into LNA/DNA strands using highly efficient copper(i)-catalyzed azide-alkyne cycloaddition (CuAAC) "click" chemistry. DNA/RNA target binding affinity and selectivity of the resulting POCs were improved in comparison to LNA/DNA mixmers and unmodified DNA controls. This clearly demonstrates that internal attachment of peptides to oligonucleotides can significantly improve biomolecular recognition by synthetic nucleic acid analogues. Circular dichroism (CD) measurements showed no distortion of the duplex structure by the incorporated peptide chains while studies in human serum indicated superior stability of the POCs compared to LNA/DNA mixmers and unmodified DNA references. Molecular modeling suggests strong interactions between positively charged regions of the peptides and the negative oligonucleotide backbones which leads to clamping of the peptides in a fixed orientation along the duplexes.
Original languageEnglish
JournalOrganic & Biomolecular Chemistry
Volume11
Issue number25
Pages (from-to)4240-4249
ISSN1477-0520
DOIs
Publication statusPublished - 2013

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Oligonucleotides
Peptides
DNA
Alkynes
Nucleic Acids
Leucine Enkephalin
Methionine Enkephalin
Molecular modeling
Azides
Cycloaddition
Scaffolds
Copper
RNA
Derivatives
Amino Acids

Cite this

Astakhova, I Kira ; Hansen, Lykke Haastrup ; Vester, Birte ; Wengel, Jesper. / Peptide-LNA oligonucleotide conjugates. In: Organic & Biomolecular Chemistry. 2013 ; Vol. 11, No. 25. pp. 4240-4249.
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title = "Peptide-LNA oligonucleotide conjugates",
abstract = "Although peptide-oligonucleotide conjugates (POCs) are well-known for nucleic acids delivery and therapy, reports on internal attachment of peptides to oligonucleotides are limited in number. To develop a convenient route for preparation of internally labeled POCs with improved biomedical properties, peptides were introduced into oligonucleotides via a 2'-alkyne-2'-amino-LNA scaffold. Derivatives of methionine- and leucine-enkephalins were chosen as model peptides of mixed amino acid content, which were singly and doubly incorporated into LNA/DNA strands using highly efficient copper(i)-catalyzed azide-alkyne cycloaddition (CuAAC) {"}click{"} chemistry. DNA/RNA target binding affinity and selectivity of the resulting POCs were improved in comparison to LNA/DNA mixmers and unmodified DNA controls. This clearly demonstrates that internal attachment of peptides to oligonucleotides can significantly improve biomolecular recognition by synthetic nucleic acid analogues. Circular dichroism (CD) measurements showed no distortion of the duplex structure by the incorporated peptide chains while studies in human serum indicated superior stability of the POCs compared to LNA/DNA mixmers and unmodified DNA references. Molecular modeling suggests strong interactions between positively charged regions of the peptides and the negative oligonucleotide backbones which leads to clamping of the peptides in a fixed orientation along the duplexes.",
author = "Astakhova, {I Kira} and Hansen, {Lykke Haastrup} and Birte Vester and Jesper Wengel",
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Peptide-LNA oligonucleotide conjugates. / Astakhova, I Kira; Hansen, Lykke Haastrup; Vester, Birte; Wengel, Jesper.

In: Organic & Biomolecular Chemistry, Vol. 11, No. 25, 2013, p. 4240-4249.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Peptide-LNA oligonucleotide conjugates

AU - Astakhova, I Kira

AU - Hansen, Lykke Haastrup

AU - Vester, Birte

AU - Wengel, Jesper

PY - 2013

Y1 - 2013

N2 - Although peptide-oligonucleotide conjugates (POCs) are well-known for nucleic acids delivery and therapy, reports on internal attachment of peptides to oligonucleotides are limited in number. To develop a convenient route for preparation of internally labeled POCs with improved biomedical properties, peptides were introduced into oligonucleotides via a 2'-alkyne-2'-amino-LNA scaffold. Derivatives of methionine- and leucine-enkephalins were chosen as model peptides of mixed amino acid content, which were singly and doubly incorporated into LNA/DNA strands using highly efficient copper(i)-catalyzed azide-alkyne cycloaddition (CuAAC) "click" chemistry. DNA/RNA target binding affinity and selectivity of the resulting POCs were improved in comparison to LNA/DNA mixmers and unmodified DNA controls. This clearly demonstrates that internal attachment of peptides to oligonucleotides can significantly improve biomolecular recognition by synthetic nucleic acid analogues. Circular dichroism (CD) measurements showed no distortion of the duplex structure by the incorporated peptide chains while studies in human serum indicated superior stability of the POCs compared to LNA/DNA mixmers and unmodified DNA references. Molecular modeling suggests strong interactions between positively charged regions of the peptides and the negative oligonucleotide backbones which leads to clamping of the peptides in a fixed orientation along the duplexes.

AB - Although peptide-oligonucleotide conjugates (POCs) are well-known for nucleic acids delivery and therapy, reports on internal attachment of peptides to oligonucleotides are limited in number. To develop a convenient route for preparation of internally labeled POCs with improved biomedical properties, peptides were introduced into oligonucleotides via a 2'-alkyne-2'-amino-LNA scaffold. Derivatives of methionine- and leucine-enkephalins were chosen as model peptides of mixed amino acid content, which were singly and doubly incorporated into LNA/DNA strands using highly efficient copper(i)-catalyzed azide-alkyne cycloaddition (CuAAC) "click" chemistry. DNA/RNA target binding affinity and selectivity of the resulting POCs were improved in comparison to LNA/DNA mixmers and unmodified DNA controls. This clearly demonstrates that internal attachment of peptides to oligonucleotides can significantly improve biomolecular recognition by synthetic nucleic acid analogues. Circular dichroism (CD) measurements showed no distortion of the duplex structure by the incorporated peptide chains while studies in human serum indicated superior stability of the POCs compared to LNA/DNA mixmers and unmodified DNA references. Molecular modeling suggests strong interactions between positively charged regions of the peptides and the negative oligonucleotide backbones which leads to clamping of the peptides in a fixed orientation along the duplexes.

U2 - 10.1039/c3ob40786a

DO - 10.1039/c3ob40786a

M3 - Journal article

VL - 11

SP - 4240

EP - 4249

JO - Organic & Biomolecular Chemistry

JF - Organic & Biomolecular Chemistry

SN - 1477-0520

IS - 25

ER -