Abstract
Aptamers constitute an answer for the growing need for targeted therapy development. One of the most well-known representatives of this group of compounds is thrombin binding aptamers (TBA) targeted towards thrombin. The TBA inhibitory activity is determined by its spatial arrangement, which consists of two G-tetrads linked by two shorter TT loops and one longer TGT loop and folds into a unimolecular, antiparallel G-quadruplex structure. Interesting properties of the aptamer can be further improved via the introduction of a number of chemical modifications. Herein, a comprehensive analysis of the influence of pyrrolo-2’-deoxycytidine (Py-dC) and its derivatives on TBA physicochemical and biological properties has been presented. The studies have shown that the presence of modified residues at the T7 position of the TGT loop has only minor effects on TBA thermodynamic stability without affecting its folding topology. All analyzed oligomers exhibit anticoagulant properties, but only aptamer modified with a decyl derivative of Py-dC was able to inhibit thrombin activity more efficiently than unmodified, parental compounds. Importantly, the same compound also possessed the potential to effectively restrain HeLa cell line growth.
Highlights
The latest trends in modern medicine rely on the recognition of a molecular basis of disease and the development of drugs based on this knowledge
The most favorable influence on anticoagulant properties of the thrombin binding aptamers (TBA) had the substitution of T7 with a decyl derivative of Py-dC containing a long aliphatic, linear side-chain
The inhibitory effect of this aptamer was improved in comparison to the parental TBA compound
Summary
The latest trends in modern medicine rely on the recognition of a molecular basis of disease and the development of drugs based on this knowledge. The group of compounds, which perfectly enroll in the above trends, are aptamers They constitute a group of single-stranded oligonucleotides, whose sequence determines folding into a peculiar tertiary structure [1]. The specific shape of aptamers ensures the high specificity and selectivity of interactions with target molecules [2,3,4]. Due to their high biological activity, ease of chemical synthesis, and advantageous dissociation constant, aptamers have found a number of potential applications in medicine, with the superior ability to be highly specific drugs characterized by reversibility of action and extended half-life
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