Duplex/quadruplex oligonucleotides: Role of the duplex domain in the stabilization of a new generation of highly effective anti-thrombin aptamers

•Conformation of duplex/quadruplex aptamers is affected by cations in solution.•Duplex and quadruplex domains affect each other stability.•Duplex domain stabilizes an active conformation in pseudo physiological conditions. [Display omitted] Recently, mixed duplex/quadruplex oligonucleotides have att...

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Published in:International journal of biological macromolecules 2018-02, Vol.107 (Pt B), p.1697-1705
Main Authors: Russo Krauss, Irene, Napolitano, Valeria, Petraccone, Luigi, Troisi, Romualdo, Spiridonova, Vera, Mattia, Carlo Andrea, Sica, Filomena
Format: Article
Language:English
Subjects:
Antithrombins - pharmacology
Aptamer
Aptamers, Nucleotide - pharmacology
Base Sequence
Bimodular aptamer
Calorimetry, Differential Scanning
Circular Dichroism
Coagulation
DNA
Duplex/quadruplex
G-quadruplex
G-Quadruplexes
Monovalent cations
Nucleic Acid Denaturation
Oligonucleotides - chemistry
Structure-function relationship
TBA
Temperature
Thrombin
Ultraviolet Rays
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Summary:•Conformation of duplex/quadruplex aptamers is affected by cations in solution.•Duplex and quadruplex domains affect each other stability.•Duplex domain stabilizes an active conformation in pseudo physiological conditions. [Display omitted] Recently, mixed duplex/quadruplex oligonucleotides have attracted great interest for use as biomedical aptamers. In the case of anti-thrombin aptamers, the addition of duplex-forming sequences to a G-quadruplex module identical or very similar to the best-known G-quadruplex of the Thrombin Binding Aptamer (HD1) results in new or improved biological properties, such as higher activity or different recognition properties with respect to HD1. Remarkably, this bimodular fold was hypothesized, based on its sequence, for the only anti-thrombin aptamer in advanced clinical trial, NU172. Whereas cation modulation of G-quadruplex conformation and stability is well characterized, only few data from similar analysis on duplex/quadruplex oligonucleotides exist. Here we have performed a characterization of structure and stability of four different duplex/quadruplex anti-thrombin aptamers, including NU172, in the presence of different cations and in physiological-mimicking conditions in comparison to HD1, by means of spectroscopic techniques (UV and circular dichroism) and differential scanning calorimetry. Our data show a strong reciprocal influence of each domain on the stability of the other and in particular suggest a stabilizing effect of the duplex region in the presence of solutions mimicking the physiological conditions, strengthening the idea that bimodular aptamers present better therapeutic potentialities than those containing a single G-quadruplex domain.
ISSN:0141-8130
1879-0003
DOI:10.1016/j.ijbiomac.2017.10.033