Journal
CHEMBIOCHEM
Volume 18, Issue 8, Pages 755-763Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cbic.201600654
Keywords
aptamers; G-quadruplex; modified DNA; thrombin; unlocked nucleic acid
Funding
- European Research Council under the European Union's Seventh Framework program FP7 [ERC 268776]
- McCusker Charitable Foundation
- Western Australian Neuroscience Research Institute
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The thrombin-binding aptamer (TBA), which shows anticoagulant properties, is one of the most studied G-quadruplex-forming aptamers. In this study, we investigated the impact of different chemical modifications such as a three-carbon spacer (spacer-C-3), unlocked nucleic acid (UNA) and 3'-amino-modified UNA (amino-UNA) on the structural dynamics and stability of TBA. All three modifications were incorporated at three different loop positions (T3, T7, T12) of the TBA G-quadruplex structure to result in a series of TBA variants and their stability was studied by thermal denaturation; folding was studied by circular dichroism spectroscopy and thrombin clotting time. The results showed that spacer-C-3 introduction at the T7 loop position (TBA-SP7) significantly improved stability and thrombin clotting time while maintaining a similar binding affinity as TBA to thrombin. Detailed molecular modelling experiments provided novel insights into the experimental observations, further supporting the efficacy of TBA-SP7. The results of this study could provide valuable information for future designs of TBA analogues with superior thrombin inhibition properties.
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