Towards Profiling of the G-Quadruplex Targeting Drugs in the Living Human Cells Using NMR Spectroscopy

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Authors

KRAFČÍK Daniel IŠTVÁNKOVÁ Eva DŽATKO Šimon VÍŠKOVÁ Pavlína FOLDYNOVA-TRANTIRKOVA S. TRANTÍREK Lukáš

Year of publication 2021
Type Article in Periodical
Magazine / Source International Journal of Molecular Sciences
MU Faculty or unit

Central European Institute of Technology

Citation
Web https://www.mdpi.com/1422-0067/22/11/6042
Doi http://dx.doi.org/10.3390/ijms22116042
Keywords in-cell NMR; G-quadruplex; ligand; drug; Bcl2; telomeric DNA; KRAS; BRACO19; PhenDC3; NMM
Description Recently, the H-1-detected in-cell NMR spectroscopy has emerged as a unique tool allowing the characterization of interactions between nucleic acid-based targets and drug-like molecules in living human cells. Here, we assess the application potential of H-1 and F-19-detected in-cell NMR spectroscopy to profile drugs/ligands targeting DNA G-quadruplexes, arguably the most studied class of anti-cancer drugs targeting nucleic acids. We show that the extension of the original in-cell NMR approach is not straightforward. The severe signal broadening and overlap of H-1 in-cell NMR spectra of polymorphic G-quadruplexes and their complexes complicate their quantitative interpretation. Nevertheless, the H-1 in-cell NMR can be used to identify drugs that, despite strong interaction in vitro, lose their ability to bind G-quadruplexes in the native environment. The in-cell NMR approach is adjusted to a recently developed 3,5-bis(trifluoromethyl)phenyl probe to monitor the intracellular interaction with ligands using F-19-detected in-cell NMR. The probe allows dissecting polymorphic mixture in terms of number and relative populations of individual G-quadruplex species, including ligand-bound and unbound forms in vitro and in cellulo. Despite the probe's discussed limitations, the F-19-detected in-cell NMR appears to be a promising strategy to profile G-quadruplex-ligand interactions in the complex environment of living cells.
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