Oligonucleotides with Cationic Backbone and Their Hybridization with DNA: Interplay of Base Pairing and Electrostatic Attraction

Boris Schmidtgall, Arne Kuepper, Melissa Meng, Tom N. Grossmann, Christian Ducho

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

Non-natural oligonucleotides represent important (bio)chemical tools and potential therapeutic agents. Backbone modifications altering hybridization properties and biostability can provide useful analogues. Here, we employ an artificial nucleosyl amino acid (NAA) motif for the synthesis of oligonucleotides containing a backbone decorated with primary amines. An oligo-T sequence of this cationic DNA analogue shows significantly increased affinity for complementary DNA. Notably, hybridization with DNA is still governed by Watson–Crick base pairing. However, single base pair mismatches are tolerated and some degree of sequence-independent interactions between the cationic NAA backbone and fully mismatched DNA are observed. These findings demonstrate that a high density of positive charges directly connected to the oligonucleotide backbone can affect Watson–Crick base pairing. This provides a paradigm for the design of therapeutic oligonucleotides with altered backbone charge patterns.

Original languageEnglish
Pages (from-to)1544-1553
Number of pages10
JournalChemistry: A European Journal
Volume24
Issue number7
Early online date19 Oct 2017
DOIs
Publication statusPublished - 1 Feb 2018

Keywords

  • backbone modifications
  • DNA
  • oligonucleotides
  • peptides
  • stereoselective synthesis

Cite this

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Oligonucleotides with Cationic Backbone and Their Hybridization with DNA : Interplay of Base Pairing and Electrostatic Attraction. / Schmidtgall, Boris; Kuepper, Arne; Meng, Melissa; Grossmann, Tom N.; Ducho, Christian.

In: Chemistry: A European Journal, Vol. 24, No. 7, 01.02.2018, p. 1544-1553.

Research output: Contribution to JournalArticleAcademicpeer-review

TY - JOUR

T1 - Oligonucleotides with Cationic Backbone and Their Hybridization with DNA

T2 - Interplay of Base Pairing and Electrostatic Attraction

AU - Schmidtgall, Boris

AU - Kuepper, Arne

AU - Meng, Melissa

AU - Grossmann, Tom N.

AU - Ducho, Christian

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N2 - Non-natural oligonucleotides represent important (bio)chemical tools and potential therapeutic agents. Backbone modifications altering hybridization properties and biostability can provide useful analogues. Here, we employ an artificial nucleosyl amino acid (NAA) motif for the synthesis of oligonucleotides containing a backbone decorated with primary amines. An oligo-T sequence of this cationic DNA analogue shows significantly increased affinity for complementary DNA. Notably, hybridization with DNA is still governed by Watson–Crick base pairing. However, single base pair mismatches are tolerated and some degree of sequence-independent interactions between the cationic NAA backbone and fully mismatched DNA are observed. These findings demonstrate that a high density of positive charges directly connected to the oligonucleotide backbone can affect Watson–Crick base pairing. This provides a paradigm for the design of therapeutic oligonucleotides with altered backbone charge patterns.

AB - Non-natural oligonucleotides represent important (bio)chemical tools and potential therapeutic agents. Backbone modifications altering hybridization properties and biostability can provide useful analogues. Here, we employ an artificial nucleosyl amino acid (NAA) motif for the synthesis of oligonucleotides containing a backbone decorated with primary amines. An oligo-T sequence of this cationic DNA analogue shows significantly increased affinity for complementary DNA. Notably, hybridization with DNA is still governed by Watson–Crick base pairing. However, single base pair mismatches are tolerated and some degree of sequence-independent interactions between the cationic NAA backbone and fully mismatched DNA are observed. These findings demonstrate that a high density of positive charges directly connected to the oligonucleotide backbone can affect Watson–Crick base pairing. This provides a paradigm for the design of therapeutic oligonucleotides with altered backbone charge patterns.

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KW - DNA

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