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Development of an Efficient G-Quadruplex-Stabilised Thrombin-Binding Aptamer Containing a Three-Carbon Spacer Molecule
KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.ORCID iD: 0000-0003-0185-5724
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2017 (English)In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 18, no 8, p. 755-763Article in journal (Refereed) Published
Abstract [en]

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-C3), 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-C3 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. © 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.

Place, publisher, year, edition, pages
Wiley-VCH Verlag , 2017. Vol. 18, no 8, p. 755-763
Keywords [en]
aptamers, G-quadruplex, modified DNA, thrombin, unlocked nucleic acid
National Category
Chemical Sciences Biological Sciences
Identifiers
URN: urn:nbn:se:kth:diva-207354DOI: 10.1002/cbic.201600654ISI: 000399686300008Scopus ID: 2-s2.0-85015193686OAI: oai:DiVA.org:kth-207354DiVA, id: diva2:1096794
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QC 20170519

Available from: 2017-05-19 Created: 2017-05-19 Last updated: 2017-06-02Bibliographically approved

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