Improved RE31 Analogues Containing Modified Nucleic Acid Monomers: Thermodynamic, Structural, and Biological Effects

Weronika Kotkowiak, Jesper Wengel, Chris J Scotton, Anna Pasternak

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

RE31 is a 31-nt DNA aptamer, consisting of the G-quadruplex and a duplex domain, which is able to effectively prolong thrombin time. This article reports on the influence of certain modified nucleotide residues on thermodynamic and biological properties as well as the folding topology of RE31. Particularly, the effect of the presence of nucleosides in unlocked nucleic acid (UNA), locked nucleic acid (LNA), or β-l-RNA series was evaluated. The studies presented herein show that all modified residues can influence thermal and biological stabilities of G-quadruplex in a position-dependent manner. The aptamers modified simultaneously with UNA at the T15 position and LNAs in the duplex part possess the highest value of melting temperature and a 2-fold higher anticoagulant effect. Importantly, RE31 variants modified with nucleosides in UNA, LNA, or β-l-RNA series exhibit unchanged G-quadruplex folding topology. Crucially, introduction of any of the modified residues into RE31 causes prolongation of aptamer stability in human serum.

Original languageEnglish
JournalJournal of Medicinal Chemistry
Volume62
Issue number5
Pages (from-to)2499-2507
ISSN0022-2623
DOIs
Publication statusPublished - 14. Mar 2019

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Nucleic Acids
Nucleotide Aptamers
RNA
Freezing
Serum

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title = "Improved RE31 Analogues Containing Modified Nucleic Acid Monomers: Thermodynamic, Structural, and Biological Effects",
abstract = "RE31 is a 31-nt DNA aptamer, consisting of the G-quadruplex and a duplex domain, which is able to effectively prolong thrombin time. This article reports on the influence of certain modified nucleotide residues on thermodynamic and biological properties as well as the folding topology of RE31. Particularly, the effect of the presence of nucleosides in unlocked nucleic acid (UNA), locked nucleic acid (LNA), or β-l-RNA series was evaluated. The studies presented herein show that all modified residues can influence thermal and biological stabilities of G-quadruplex in a position-dependent manner. The aptamers modified simultaneously with UNA at the T15 position and LNAs in the duplex part possess the highest value of melting temperature and a 2-fold higher anticoagulant effect. Importantly, RE31 variants modified with nucleosides in UNA, LNA, or β-l-RNA series exhibit unchanged G-quadruplex folding topology. Crucially, introduction of any of the modified residues into RE31 causes prolongation of aptamer stability in human serum.",
author = "Weronika Kotkowiak and Jesper Wengel and Scotton, {Chris J} and Anna Pasternak",
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Improved RE31 Analogues Containing Modified Nucleic Acid Monomers : Thermodynamic, Structural, and Biological Effects. / Kotkowiak, Weronika; Wengel, Jesper; Scotton, Chris J; Pasternak, Anna.

In: Journal of Medicinal Chemistry, Vol. 62, No. 5, 14.03.2019, p. 2499-2507.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Improved RE31 Analogues Containing Modified Nucleic Acid Monomers

T2 - Thermodynamic, Structural, and Biological Effects

AU - Kotkowiak, Weronika

AU - Wengel, Jesper

AU - Scotton, Chris J

AU - Pasternak, Anna

PY - 2019/3/14

Y1 - 2019/3/14

N2 - RE31 is a 31-nt DNA aptamer, consisting of the G-quadruplex and a duplex domain, which is able to effectively prolong thrombin time. This article reports on the influence of certain modified nucleotide residues on thermodynamic and biological properties as well as the folding topology of RE31. Particularly, the effect of the presence of nucleosides in unlocked nucleic acid (UNA), locked nucleic acid (LNA), or β-l-RNA series was evaluated. The studies presented herein show that all modified residues can influence thermal and biological stabilities of G-quadruplex in a position-dependent manner. The aptamers modified simultaneously with UNA at the T15 position and LNAs in the duplex part possess the highest value of melting temperature and a 2-fold higher anticoagulant effect. Importantly, RE31 variants modified with nucleosides in UNA, LNA, or β-l-RNA series exhibit unchanged G-quadruplex folding topology. Crucially, introduction of any of the modified residues into RE31 causes prolongation of aptamer stability in human serum.

AB - RE31 is a 31-nt DNA aptamer, consisting of the G-quadruplex and a duplex domain, which is able to effectively prolong thrombin time. This article reports on the influence of certain modified nucleotide residues on thermodynamic and biological properties as well as the folding topology of RE31. Particularly, the effect of the presence of nucleosides in unlocked nucleic acid (UNA), locked nucleic acid (LNA), or β-l-RNA series was evaluated. The studies presented herein show that all modified residues can influence thermal and biological stabilities of G-quadruplex in a position-dependent manner. The aptamers modified simultaneously with UNA at the T15 position and LNAs in the duplex part possess the highest value of melting temperature and a 2-fold higher anticoagulant effect. Importantly, RE31 variants modified with nucleosides in UNA, LNA, or β-l-RNA series exhibit unchanged G-quadruplex folding topology. Crucially, introduction of any of the modified residues into RE31 causes prolongation of aptamer stability in human serum.

U2 - 10.1021/acs.jmedchem.8b01806

DO - 10.1021/acs.jmedchem.8b01806

M3 - Journal article

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JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 5

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