Development of an Efficient G-Quadruplex-Stabilised Thrombin-Binding Aptamer Containing a Three-Carbon Spacer Molecule

Aaldering, L. J. (author)

Poongavanam, V. (author)

Langkjær, N. (author)

Jørgensen, P. T. (author)

Wengel, J. (author)

Veedu, R. N. (author)

(creator_code:org_t)

2017-03-15
2017
English.
In: ChemBioChem. - : Wiley-VCH Verlag. - 1439-4227 .- 1439-7633. ; 18:8, s. 755-763

Related links:: https://doi.org/10.1...; show more...; https://doi.org/10.1...; https://urn.kb.se/re...; https://doi.org/10.1...; show less...

Abstract Subject headings

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.

By the author/editor: Aaldering, L. J.; Poongavanam, V.; Langkjær, N.; Natarajan Arul, ...; Jørgensen, P. T.; Wengel, J.; show more...; Veedu, R. N.; show less...

About the subject

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