Expanding the Potential of G‐Quadruplex Structures: Formation of a Heterochiral TBA Analogue

Abstract

In order to expand the potential applications of G-quadruplex structures, we explored the ability of heterochiral oligodeoxynucleotides based on the thrombin-binding aptamer (TBA) sequence to fold into similar complexes, with particular focus on their resistance in biological environments. A combination of CD and NMR techniques was used. Similarly to TBA, the ODN ggTTggtgtggTTgg (lower case letters indicate L residues) is able to fold into a chair-like antiparallel G-quadruplex structure, but has a slightly higher thermal stability. The discovery that heterochiral ODNs are able to form stable G-quadruplex structures opens up new possibilities for their development in several fields, as aptamers, sensors and, as recently shown, as catalysts for enantioselective reactions.

uL3 Mediated Nucleolar Stress Pathway as a New Mechanism of Action of Antiproliferative G-quadruplex TBA Derivatives in Colon Cancer Cells

“…As previously reported [28], L-TBA shows a CD profile completely specular to that of its unmodified analog, thus indicating that this ODN adopts a left-handed chair-like G-quadruplex structure that is the mirror image of the TBA structure, as expected. Although the sequences of the other modified differ from L-TBA in the D/L-residues composition of the loop (Table 1), their CD spectra show profiles very similar to that of L-TBA, except for slight differences in the band intensities more marked for LQ2 and LQ3.…”

“…The estimated melting temperatures (T m ) are listed in Table 1. A comparison of data here and previously reported [28] shows that T m of all modified analogs is quite similar to that of the parent aptamer. Noticeably, LQ1 exhibits a slightly higher thermal stability (52 • C) than the unmodified TBA (Table 1).…”

“…In 2017, we described the antiproliferative activity of several TBA derivatives against two different cancer cell lines, namely Calu-6 and HCT 116 p53−/− [11]. Two of these previously investigated TBA derivatives attracted our attention, specifically L-TBA, composed exclusively by L-residues, and LQ1 (formerly D13), composed by L-nucleosides except for those ones in the small loops ( Table 1), considering that they possess no anticoagulant activity and have shown exceptional resistance to nucleases [28].…”

The effect of l-thymidine, acyclic thymine and 8-bromoguanine on the stability of model G-quadruplex structures

“…TDS of TBA7LT is similar to TBA and TBA3LT is the most featureless. The modification with multiple Lderivatives in the tetrads and in the loops of TBA has been studied in the bibliography [25].…”

“…L-thymidine has been introduced in a tetramolecular G-quadruplex [TG 4 T] 4 [23] or in a monomolecular G-quadruplex such as anti-HIV aptamer [24] or TBA [25]. In addition, TBA has been modified with enantiomeric nucleosides in different positions.…”