Peptide-LNA oligonucleotide conjugates

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

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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 and Biomolecular Chemistry
Volume11
Issue number25
Pages (from-to)4240-4249
Number of pages10
ISSN1477-0520
DOIs
Publication statusPublished - 2013
Externally publishedYes

Bibliographical note

Open Access Article. This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence.

Keywords

  • CHEMISTRY,
  • AZIDE-ALKYNE CYCLOADDITION
  • LOCKED NUCLEIC-ACIDS
  • TERMINAL ALKYNES
  • CLICK CHEMISTRY
  • MAJOR GROOVE
  • FORCE-FIELD
  • DNA
  • RECOGNITION
  • STABILITY
  • COMPLEX
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Biochemistry
  • Biomedical properties
  • Biomolecular recognition
  • Copper(i) catalyzed azide alkyne cycloaddition (CuAAC)
  • Nucleic acids deliveries
  • Oligonucleotide conjugates
  • Positively charged
  • Strong interaction
  • Synthetic nucleic acid
  • Amino acids
  • Binding energy
  • Hydrocarbons
  • Molecular recognition
  • Nucleic acids
  • Oligonucleotides
  • Scaffolds
  • Peptides
  • enkephalin
  • locked nucleic acid
  • oligonucleotide
  • amino acid sequence
  • article
  • chemical structure
  • chemistry
  • click chemistry
  • human
  • metabolism
  • nucleotide sequence
  • serum
  • Amino Acid Sequence
  • Base Sequence
  • Click Chemistry
  • Enkephalins
  • Humans
  • Models, Molecular
  • Serum

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