Improving Structural Stability and Anticoagulant Activity of a Thrombin Binding Aptamer by Aromatic Modifications

Nathalie Busschaert; Debabrata Maity; Pralok K. Samanta; Niall J. English; Andrew D. Hamilton

doi:10.1002/cbic.202100670

Improving Structural Stability and Anticoagulant Activity of a Thrombin Binding Aptamer by Aromatic Modifications

Nathalie Busschaert, Debabrata Maity, Pralok K. Samanta, Niall J. English, Andrew D. Hamilton

Chemistry

Research output: Contribution to journal › Article › peer-review

Abstract

The thrombin binding aptamer (TBA) is a 15-mer DNA oligonucleotide (5′-GGT TGG TGT GGT TGG-3′), that can form a stable intramolecular antiparallel chair-like G-quadruplex structure. This aptamer shows anticoagulant properties by interacting with one of the two anion binding sites of thrombin, namely the fibrinogen-recognition exosite. Here, we demonstrate that terminal modification of TBA with aromatic fragments such as coumarin, pyrene and perylene diimide (PDI), improves the G-quadruplex stability. The large aromatic surface of these dyes can π-π stack to the G-quadruplex or to each other, thereby stabilizing the aptamer. With respect to the original TBA, monoPDI-functionalized TBA exhibited the most remarkable improvement in melting temperature (ΔT_m≈+18 °C) and displayed enhanced anticoagulant activity.

Original language	English (US)
Article number	e202100670
Journal	ChemBioChem
Volume	23
Issue number	6
DOIs	https://doi.org/10.1002/cbic.202100670
State	Published - Mar 18 2022

Keywords

G-quadruplexes
anticoagulants
aptamers
supramolecular chemistry
π-π stacking

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Organic Chemistry

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10.1002/cbic.202100670

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title = "Improving Structural Stability and Anticoagulant Activity of a Thrombin Binding Aptamer by Aromatic Modifications",

abstract = "The thrombin binding aptamer (TBA) is a 15-mer DNA oligonucleotide (5′-GGT TGG TGT GGT TGG-3′), that can form a stable intramolecular antiparallel chair-like G-quadruplex structure. This aptamer shows anticoagulant properties by interacting with one of the two anion binding sites of thrombin, namely the fibrinogen-recognition exosite. Here, we demonstrate that terminal modification of TBA with aromatic fragments such as coumarin, pyrene and perylene diimide (PDI), improves the G-quadruplex stability. The large aromatic surface of these dyes can π-π stack to the G-quadruplex or to each other, thereby stabilizing the aptamer. With respect to the original TBA, monoPDI-functionalized TBA exhibited the most remarkable improvement in melting temperature (ΔTm≈+18 °C) and displayed enhanced anticoagulant activity.",

keywords = "G-quadruplexes, anticoagulants, aptamers, supramolecular chemistry, π-π stacking",

author = "Nathalie Busschaert and Debabrata Maity and Samanta, {Pralok K.} and English, {Niall J.} and Hamilton, {Andrew D.}",

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AU - Busschaert, Nathalie

AU - Maity, Debabrata

AU - Samanta, Pralok K.

AU - English, Niall J.

AU - Hamilton, Andrew D.

PY - 2022/3/18

Y1 - 2022/3/18

N2 - The thrombin binding aptamer (TBA) is a 15-mer DNA oligonucleotide (5′-GGT TGG TGT GGT TGG-3′), that can form a stable intramolecular antiparallel chair-like G-quadruplex structure. This aptamer shows anticoagulant properties by interacting with one of the two anion binding sites of thrombin, namely the fibrinogen-recognition exosite. Here, we demonstrate that terminal modification of TBA with aromatic fragments such as coumarin, pyrene and perylene diimide (PDI), improves the G-quadruplex stability. The large aromatic surface of these dyes can π-π stack to the G-quadruplex or to each other, thereby stabilizing the aptamer. With respect to the original TBA, monoPDI-functionalized TBA exhibited the most remarkable improvement in melting temperature (ΔTm≈+18 °C) and displayed enhanced anticoagulant activity.

AB - The thrombin binding aptamer (TBA) is a 15-mer DNA oligonucleotide (5′-GGT TGG TGT GGT TGG-3′), that can form a stable intramolecular antiparallel chair-like G-quadruplex structure. This aptamer shows anticoagulant properties by interacting with one of the two anion binding sites of thrombin, namely the fibrinogen-recognition exosite. Here, we demonstrate that terminal modification of TBA with aromatic fragments such as coumarin, pyrene and perylene diimide (PDI), improves the G-quadruplex stability. The large aromatic surface of these dyes can π-π stack to the G-quadruplex or to each other, thereby stabilizing the aptamer. With respect to the original TBA, monoPDI-functionalized TBA exhibited the most remarkable improvement in melting temperature (ΔTm≈+18 °C) and displayed enhanced anticoagulant activity.

KW - G-quadruplexes

KW - anticoagulants

KW - aptamers

KW - supramolecular chemistry

KW - π-π stacking

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Improving Structural Stability and Anticoagulant Activity of a Thrombin Binding Aptamer by Aromatic Modifications

Abstract

Keywords

ASJC Scopus subject areas

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