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Thermodynamic, Anticoagulant, and Antiproliferative Properties of Thrombin Binding Aptamer Containing Novel UNA Derivative
Abstract
Thrombin is a serine protease that plays a crucial role in hemostasis, fibrinolysis, cell proliferation, and migration. Thrombin binding aptamer (TBA) is able to inhibit the activity of thrombin molecule via binding to its exosite I. This 15-nt DNA oligonucleotide forms an intramolecular, antiparallel G-quadruplex structure with a chair-like conformation. In this paper, we report on our investigations on the influence of certain modified nucleotide residues on thermodynamic stability, folding topology, and biological properties of TBA variants. In particular, the effect of single incorporation of a novel 4-thiouracil derivative of unlocked nucleic acid (UNA), as well as single incorporation of 4-thiouridine and all four canonical UNAs, was evaluated. The studies presented herein have shown that 4-thiouridine in RNA and UNA series, as well as all four canonical UNAs, can efficiently modulate G-quadruplex thermodynamic and biological stability, and that the effect is strongly position dependent. Interestingly, TBA variants containing the modified nucleotide residues are characterized by unchanged folding topology. Thrombin time assay revealed that incorporation of certain UNA residues may improve G-quadruplex anticoagulant properties. Noteworthy, some TBA variants, characterized by decreased ability to inhibit thrombin activity, possess significant antiproliferative properties reducing the viability of the HeLa cell line even by 95% at 10 μM concentration.
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Authors (6)
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Weronika Kotkowiak dr
- Instytut Chemii Bioorganicznej Polskiej Akademii Nauk Zakład Bioinżynierii Kwasów Nukleinowych
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Jolanta Lisowiec-Wachnicka dr
- Instytut Chemii Bioorganicznej Polskiej Akademii Nauk Zakład Bioinżynierii Kwasów Nukleinowych
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Ryszard Kierzek prof. dr hab.
- Instytut Chemii Bioorganicznej Polskiej Akademii Nauk Zakład Chemii i Biologii Strukturalnej Kwasów Nukleinowych
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Jesper Wengel doktor
- University of Southern Denmark Department of Physics, Chemistry and Pharmacy
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Anna Pasternak dr hab.
- Instytut Chemii Bioorganicznej Polskiej Akademii Nauk Zakład Bioinżynierii Kwasów Nukleinowych
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Keywords
Details
- Category:
- Articles
- Type:
- artykuł w czasopiśmie wyróżnionym w JCR
- Published in:
-
Molecular Therapy-Nucleic Acids
no. 10,
pages 304 - 316,
ISSN: 2162-2531 - Language:
- English
- Publication year:
- 2018
- Bibliographic description:
- Kotkowiak W., Lisowiec-Wachnicka J., Grynda J., Kierzek R., Wengel J., Pasternak A.: Thermodynamic, Anticoagulant, and Antiproliferative Properties of Thrombin Binding Aptamer Containing Novel UNA Derivative// Molecular Therapy-Nucleic Acids. -Vol. 10, (2018), s.304-316
- DOI:
- Digital Object Identifier (open in new tab) 10.1016/j.omtn.2017.12.013
- Verified by:
- Gdańsk University of Technology
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