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

J 2021

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

KRAFČÍK, Daniel, Eva IŠTVÁNKOVÁ, Šimon DŽATKO, Pavlína VÍŠKOVÁ, S. FOLDYNOVA-TRANTIRKOVA et. al.

Basic information

Original name

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

Authors

KRAFČÍK, Daniel (703 Slovakia, belonging to the institution), Eva IŠTVÁNKOVÁ (203 Czech Republic, belonging to the institution), Šimon DŽATKO (703 Slovakia, belonging to the institution), Pavlína VÍŠKOVÁ (203 Czech Republic, belonging to the institution), S. FOLDYNOVA-TRANTIRKOVA and Lukáš TRANTÍREK (203 Czech Republic, guarantor, belonging to the institution)

Edition

International Journal of Molecular Sciences, Basel, Multidisciplinary Digital Publishing Institute, 2021, 1422-0067

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

10608 Biochemistry and molecular biology

Country of publisher

Switzerland

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 6.208

RIV identification code

RIV/00216224:14740/21:00120234

Organization unit

Central European Institute of Technology

DOI

http://dx.doi.org/10.3390/ijms22116042

UT WoS

000660126000001

Keywords in English

in-cell NMR; G-quadruplex; ligand; drug; Bcl2; telomeric DNA; KRAS; BRACO19; PhenDC3; NMM

Abstract

V originále

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.

Links

NV19-08-00450, research and development project

Name: Atomárně rozlišená NMR spektroskopie in vivo jako nástroj pro biologické testování terapeuticky významných cílů v genomové ne-kanonické DNA a jejich interakcí s léčivy ve fenotypově diverzifikovaných nádorových buňkách.

Investor: Ministry of Health of the CR

90127, large research infrastructures

Name: CIISB II

Citovat

KRAFČÍK, Daniel, Eva IŠTVÁNKOVÁ, Šimon DŽATKO, Pavlína VÍŠKOVÁ, S. FOLDYNOVA-TRANTIRKOVA and Lukáš TRANTÍREK. Towards Profiling of the G-Quadruplex Targeting Drugs in the Living Human Cells Using NMR Spectroscopy. International Journal of Molecular Sciences. Basel: Multidisciplinary Digital Publishing Institute, 2021, vol. 22, No 11, p. 6042-6055. ISSN 1422-0067. Available from: https://dx.doi.org/10.3390/ijms22116042.

@article{1838631,
   author = {Krafčík, Daniel and Ištvánková, Eva and Džatko, Šimon and Víšková, Pavlína and FoldynovaandTrantirkova, S. and Trantírek, Lukáš},
   article_location = {Basel},
   article_number = {11},
   doi = {http://dx.doi.org/10.3390/ijms22116042},
   keywords = {in-cell NMR; G-quadruplex; ligand; drug; Bcl2; telomeric DNA; KRAS; BRACO19; PhenDC3; NMM},
   language = {eng},
   issn = {1422-0067},
   journal = {International Journal of Molecular Sciences},
   title = {Towards Profiling of the G-Quadruplex Targeting Drugs in the Living Human Cells Using NMR Spectroscopy},
   url = {https://www.mdpi.com/1422-0067/22/11/6042},
   volume = {22},
   year = {2021}
}

TY  - JOUR
ID  - 1838631
AU  - Krafčík, Daniel - Ištvánková, Eva - Džatko, Šimon - Víšková, Pavlína - Foldynova-Trantirkova, S. - Trantírek, Lukáš
PY  - 2021
TI  - Towards Profiling of the G-Quadruplex Targeting Drugs in the Living Human Cells Using NMR Spectroscopy
JF  - International Journal of Molecular Sciences
VL  - 22
IS  - 11
SP  - 6042
EP  - 6042
PB  - Multidisciplinary Digital Publishing Institute
SN  - 14220067
KW  - in-cell NMR
KW  - G-quadruplex
KW  - ligand
KW  - drug
KW  - Bcl2
KW  - telomeric DNA
KW  - KRAS
KW  - BRACO19
KW  - PhenDC3
KW  - NMM
UR  - https://www.mdpi.com/1422-0067/22/11/6042
N2  - 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.
ER  -

KRAFČÍK, Daniel, Eva IŠTVÁNKOVÁ, Šimon DŽATKO, Pavlína VÍŠKOVÁ, S. FOLDYNOVA-TRANTIRKOVA and Lukáš TRANTÍREK. Towards Profiling of the G-Quadruplex Targeting Drugs in the Living Human Cells Using NMR Spectroscopy. \textit{International Journal of Molecular Sciences}. Basel: Multidisciplinary Digital Publishing Institute, 2021, vol.~22, No~11, p.~6042-6055. ISSN~1422-0067. Available from: https://dx.doi.org/10.3390/ijms22116042.

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