Synthesis of peptide-oligonucleotide conjugates with single and multiple peptides attached to 2′-aldehydes through thiazolidine, oxime, and hydrazine linkages

Timofei S. Zatsepin, Dmitry A. Stetsenko, Andrey A. Arzumanov, Elena A. Romanova, Michael J. Gait, Tatiana S. Oretskaya

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113 Citations (Scopus)

Abstract

2′-Deoxyoligonucleotides and 2′-O-methyloligoribonucleotides carrying one or more 2′-aldehyde groups were synthesized and coupled to peptides containing an N-terminal cysteine, aminooxy, or hydrazide group to give peptide-oligonucleotide conjugates incorporating single or multiple peptides in good yield. The facile conjugation method allows specific coupling in aqueous solution of unprotected oligonucleotides containing aldehyde groups to unprotected N-terminally modified peptides and other small molecules. A 12-mer 2′-O-methyloligoribonucleotide complementary to the HIV-1 TAR RNA stem-loop and containing two conjugated copies of an 8-mer model laminin peptide was hardly affected in TAR RNA binding and showed a similar level of inhibition of HIV-1 Tat-dependent in vitro transcription compared to the unconjugated 2′-O-methyloligoribonucleotide. Advantages of this conjugation method include (1) the ability to attach more than one peptide or other small molecule to oligonucleotide at defined nucleoside residue locations; (2) a conjugation route that does not affect significantly oligonucleotide binding to RNA structures; and (3) three alternative, facile, and mild conjugation reaction types that do not require use of a large excess of peptide reagent.

Original languageEnglish
Pages (from-to)822-830
Number of pages9
JournalBioconjugate Chemistry
Volume13
Issue number4
DOIs
Publication statusPublished - 2002
Externally publishedYes

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