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

doi:10.1002/chem.201704338

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

^*Corresponding author for this work

AIMMS

Research output: Contribution to Journal › Article › Academic › peer-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 language	English
Pages (from-to)	1544-1553
Number of pages	10
Journal	Chemistry: A European Journal
Volume	24
Issue number	7
Early online date	19 Oct 2017
DOIs	https://doi.org/10.1002/chem.201704338
Publication status	Published - 1 Feb 2018

Funding

We thank the group of Prof. Roland Winter (TU Dortmund) for access to their CD spectrometer and the Deutsche Forschungsgemeinschaft (DFG, grant DU 1095/2-1, Emmy Noether program GR 3592/2-1) as well as the Fonds der Chemischen Industrie (FCI, Sachkostenzuschuss) for financial support. B.S. is grateful for a doctoral fellowship of the Studienstiftung des deutschen Volkes. This work was supported by AstraZeneca, Bayer CropScience, Bayer HealthCare, Boehringer Ingelheim, Merck KGaA, and the Max Planck Society. We thank the group of Prof. Roland Winter (TU Dortmund) for access to their CD spectrometer and the Deutsche Forschungs-gemeinschaft (DFG, grant DU 1095/2-1, Emmy Noether program GR 3592/2-1) as well as the Fonds der Chemischen Indus- trie (FCI, Sachkostenzuschuss) for financial support. B.S. is grateful for a doctoral fellowship of the Studienstiftung des deutschen Volkes. This work was supported by AstraZeneca, Bayer CropScience, Bayer HealthCare, Boehringer Ingelheim, Merck KGaA, and the Max Planck Society.

Funders	Funder number
Fonds der Chemischen Indus- trie
Boehringer Ingelheim
AstraZeneca
Boehringer Ingelheim
Bayer CropScience
Merck KGaA
Bayer HealthCare
Deutsche Forschungsgemeinschaft	GR 3592/2-1, DU 1095/2-1
Max-Planck-Gesellschaft
Studienstiftung des Deutschen Volkes

Keywords

backbone modifications
DNA
oligonucleotides
peptides
stereoselective synthesis

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10.1002/chem.201704338

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title = "Oligonucleotides with Cationic Backbone and Their Hybridization with DNA: Interplay of Base Pairing and Electrostatic Attraction",

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.",

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

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