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Thermodynamic and biological evaluation of a thrombin binding aptamer modified with several unlocked nucleic acid (UNA) monomers and a 2′-C-piperazino-UNA monomer. / Jensen, Troels B.; Henriksen, Jonas Rosager; Rasmussen, Bjarne E.; Rasmussen, Lars M.; Andresen, Thomas Lars; Wengel, Jesper; Pasternak, Anna.

In: Bioorganic & Medicinal Chemistry, Vol. 19, No. 16, 2011, p. 4739-4745.

Publication: Research - peer-reviewJournal article – Annual report year: 2011

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Jensen, Troels B.; Henriksen, Jonas Rosager; Rasmussen, Bjarne E.; Rasmussen, Lars M.; Andresen, Thomas Lars; Wengel, Jesper; Pasternak, Anna / Thermodynamic and biological evaluation of a thrombin binding aptamer modified with several unlocked nucleic acid (UNA) monomers and a 2′-C-piperazino-UNA monomer.

In: Bioorganic & Medicinal Chemistry, Vol. 19, No. 16, 2011, p. 4739-4745.

Publication: Research - peer-reviewJournal article – Annual report year: 2011

Bibtex

@article{3add25ffa3674d629d8980c4440ece62,
title = "Thermodynamic and biological evaluation of a thrombin binding aptamer modified with several unlocked nucleic acid (UNA) monomers and a 2′-C-piperazino-UNA monomer",
keywords = "Unlocked nucleic acid, Thermodynamics, Isothermal titration calorimetry, Thrombin binding aptamer, Thrombin time assay",
publisher = "Pergamon",
author = "Jensen, {Troels B.} and Henriksen, {Jonas Rosager} and Rasmussen, {Bjarne E.} and Rasmussen, {Lars M.} and Andresen, {Thomas Lars} and Jesper Wengel and Anna Pasternak",
year = "2011",
doi = "10.1016/j.bmc.2011.06.087",
volume = "19",
number = "16",
pages = "4739--4745",
journal = "Bioorganic & Medicinal Chemistry",
issn = "0968-0896",

}

RIS

TY - JOUR

T1 - Thermodynamic and biological evaluation of a thrombin binding aptamer modified with several unlocked nucleic acid (UNA) monomers and a 2′-C-piperazino-UNA monomer

A1 - Jensen,Troels B.

A1 - Henriksen,Jonas Rosager

A1 - Rasmussen,Bjarne E.

A1 - Rasmussen,Lars M.

A1 - Andresen,Thomas Lars

A1 - Wengel,Jesper

A1 - Pasternak,Anna

AU - Jensen,Troels B.

AU - Henriksen,Jonas Rosager

AU - Rasmussen,Bjarne E.

AU - Rasmussen,Lars M.

AU - Andresen,Thomas Lars

AU - Wengel,Jesper

AU - Pasternak,Anna

PB - Pergamon

PY - 2011

Y1 - 2011

N2 - Thrombin binding aptamer is a DNA 15-mer which forms a G-quadruplex structure and possess promising anticoagulant properties due to specific interactions with thrombin. Herein we present the influence of a single 2′-C-piperazino-UNA residue and UNA residues incorporated in several positions on thermodynamics, kinetics and biological properties of the aptamer. 2′-C-Piperazino-UNA is characterized by more efficient stabilization of quadruplex structure in comparison to regular UNA and increases thermodynamic stability of TBA by 0.28–0.44kcal/mol in a position depending manner with retained quadruplex topology and molecularity. The presence of UNA-U in positions U3, U7, and U12 results in the highest stabilization of G-quadruplex structure (ΔΔG37°=−1.03kcal/mol). On the contrary, the largest destabilization mounting to 1.79kcal/mol was observed when UNA residues were placed in positions U7, G8, and U9. Kinetic studies indicate no strict correlation between thermodynamic stability of modified variants and their binding affinity to thrombin. Most of the studied variants bind thrombin, albeit with decreased affinity in reference to unmodified TBA. Thrombin time assay studies indicate three variants as being as potent as TBA in fibrin clotting inhibition.

AB - Thrombin binding aptamer is a DNA 15-mer which forms a G-quadruplex structure and possess promising anticoagulant properties due to specific interactions with thrombin. Herein we present the influence of a single 2′-C-piperazino-UNA residue and UNA residues incorporated in several positions on thermodynamics, kinetics and biological properties of the aptamer. 2′-C-Piperazino-UNA is characterized by more efficient stabilization of quadruplex structure in comparison to regular UNA and increases thermodynamic stability of TBA by 0.28–0.44kcal/mol in a position depending manner with retained quadruplex topology and molecularity. The presence of UNA-U in positions U3, U7, and U12 results in the highest stabilization of G-quadruplex structure (ΔΔG37°=−1.03kcal/mol). On the contrary, the largest destabilization mounting to 1.79kcal/mol was observed when UNA residues were placed in positions U7, G8, and U9. Kinetic studies indicate no strict correlation between thermodynamic stability of modified variants and their binding affinity to thrombin. Most of the studied variants bind thrombin, albeit with decreased affinity in reference to unmodified TBA. Thrombin time assay studies indicate three variants as being as potent as TBA in fibrin clotting inhibition.

KW - Unlocked nucleic acid

KW - Thermodynamics

KW - Isothermal titration calorimetry

KW - Thrombin binding aptamer

KW - Thrombin time assay

U2 - 10.1016/j.bmc.2011.06.087

DO - 10.1016/j.bmc.2011.06.087

JO - Bioorganic & Medicinal Chemistry

JF - Bioorganic & Medicinal Chemistry

SN - 0968-0896

IS - 16

VL - 19

SP - 4739

EP - 4745

ER -