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Oligonucleotide conjugation to a cell-penetrating (TAT) peptide by Diels-Alder cycloaddition.

Abstract
Modifed oligonucleotides are routinely employed as analytical probes for use in diagnostics, e.g. in the examination of specific RNA sequences for infectious diseases, however, a major limiting factor in oligonucleotide-based diagnostics is poor cellular uptake of naked oligonucleotides. This problem can be overcome by covalent attachment of a so-called 'cell-penetrating peptide' to form an oligonucleotide peptide conjugate. Stepwise solid phase synthesis of such a conjugate is difficult and expensive due to the conflicting chemistries of oligonucleotides and peptides. A simple approach to overcome this is post-synthetic conjugation. Diels-Alder cycloaddition is an attractive methodology for oligonucleotide peptide conjugation; the reaction is fast, chemoselective and the reaction rate is greatly enhanced in aqueous media - ideal conditions for biological moieties. An oligodeoxyribonucleotide sequence has been derivatised with a series of dienes at the 5'-terminus, using a series of unique dienyl-modified phosphoramidites, and investigation into the effect of diene type on the efficiency of conjugation, using Diels-Alder cycloaddition with a maleimido-derivatised cell-penetrating (TAT) peptide, has been performed. This led to the observation that the optimal diene for conjugation was cyclohexadiene, allowing conjugation of oligodeoxyribonucleotides to a cell-penetrating peptide by Diels-Alder cycloaddition for the first time.
AuthorsVictoria Steven, Duncan Graham
JournalOrganic & biomolecular chemistry (Org Biomol Chem) Vol. 6 Issue 20 Pg. 3781-7 (Oct 21 2008) ISSN: 1477-0539 [Electronic] England
PMID18843408 (Publication Type: Journal Article)
Chemical References
  • Amino Acids
  • Maleimides
  • Oligodeoxyribonucleotides
  • Peptide Fragments
  • tat Gene Products, Human Immunodeficiency Virus
Topics
  • Amino Acids
  • Base Sequence
  • Cells (metabolism)
  • Maleimides (chemistry)
  • Oligodeoxyribonucleotides (chemical synthesis, chemistry, genetics, metabolism)
  • Peptide Fragments (chemistry, metabolism)
  • Permeability
  • tat Gene Products, Human Immunodeficiency Virus (chemistry, metabolism)

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