Thrombin binding aptamer G-quadruplex stabilized by pyrene-modified nucleotides
Open Access
- 25 February 2020
- journal article
- research article
- Published by Oxford University Press (OUP) in Nucleic Acids Research
- Vol. 48 (7), 3975-3986
- https://doi.org/10.1093/nar/gkaa118
Abstract
Guanine-rich regions of the human genome can adopt non-canonical secondary structures. Their role in regulating gene expression has turned them into promising targets for therapeutic intervention. Ligands based on polyaromatic moieties are especially suitable for targeting G-quadruplexes utilizing their size complementarity to interact with the large exposed surface area of four guanine bases. A predictable way of (de)stabilizing specific G-quadruplex structures through efficient base stacking of polyaromatic functional groups could become a valuable tool in our therapeutic arsenal. We have investigated the effect of pyrene-modified uridine nucleotides incorporated at several positions of the thrombin binding aptamer (TBA) as a model system. Characterization using spectroscopic and biophysical methods provided important insights into modes of interaction between pyrene groups and the G-quadruplex core as well as (de)stabilization by enthalpic and entropic contributions. NMR data demonstrated that incorporation of pyrene group into G-rich oligonucleotide such as TBA may result in significant changes in 3D structure such as formation of novel dimeric topology. Site specific structural changes induced by stacking of the pyrene moiety on nearby nucleobases corelate with distinct thrombin binding affinities and increased resistance against nuclease degradation.Funding Information
- Slovenian Research Agency (P1-0242, J1-1704)
- Japan Society for the Promotion of Science
- Ministry of Education, Science and Sport
- Ministry of Education, Culture, Sports, Science and Technology
- JSPS
- JSPS KAKENHI (JP17H06351)
- Hirao Taro Foundation of KONAN GAKUEN for Academic Research
- Okazaki Kazuo Foundation of Konan Gakuen for Advanced Scientific Research
- Chubei Itoh Foundation
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