Improved RE31 Analogues Containing Modified Nucleic Acid Monomers: Thermodynamic, Structural, and Biological Effects

Weronika Kotkowiak, Jesper Wengel, Chris J Scotton, Anna Pasternak

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Abstrakt

RE31 is a 31-nt DNA aptamer, consisting of the G-quadruplex and a duplex domain, which is able to effectively prolong thrombin time. This article reports on the influence of certain modified nucleotide residues on thermodynamic and biological properties as well as the folding topology of RE31. Particularly, the effect of the presence of nucleosides in unlocked nucleic acid (UNA), locked nucleic acid (LNA), or β-l-RNA series was evaluated. The studies presented herein show that all modified residues can influence thermal and biological stabilities of G-quadruplex in a position-dependent manner. The aptamers modified simultaneously with UNA at the T15 position and LNAs in the duplex part possess the highest value of melting temperature and a 2-fold higher anticoagulant effect. Importantly, RE31 variants modified with nucleosides in UNA, LNA, or β-l-RNA series exhibit unchanged G-quadruplex folding topology. Crucially, introduction of any of the modified residues into RE31 causes prolongation of aptamer stability in human serum.

OriginalsprogEngelsk
TidsskriftJournal of Medicinal Chemistry
Vol/bind62
Udgave nummer5
Sider (fra-til)2499-2507
ISSN0022-2623
DOI
StatusUdgivet - 14. mar. 2019

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