دورية أكاديمية
Monitoring DNA-Ligand Interactions in Living Human Cells Using NMR Spectroscopy.
| العنوان: | Monitoring DNA-Ligand Interactions in Living Human Cells Using NMR Spectroscopy. |
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| المؤلفون: | Krafcikova M; Central European Institute of Technology, Masaryk University , Brno 62500 , Czech Republic.; Institute of Biophysics , v.v.i., ASCR, Brno 62500 , Czech Republic., Dzatko S; Central European Institute of Technology, Masaryk University , Brno 62500 , Czech Republic., Caron C; CNRS UMR9187, INSERM U1196, Institut Curie , PSL Research University , Orsay 91405 , France.; CNRS UMR9187, INSERM U1196, Université Paris Sud , Université Paris Saclay , Orsay 91405 , France., Granzhan A; CNRS UMR9187, INSERM U1196, Institut Curie , PSL Research University , Orsay 91405 , France.; CNRS UMR9187, INSERM U1196, Université Paris Sud , Université Paris Saclay , Orsay 91405 , France., Fiala R; Central European Institute of Technology, Masaryk University , Brno 62500 , Czech Republic., Loja T; Central European Institute of Technology, Masaryk University , Brno 62500 , Czech Republic., Teulade-Fichou MP; CNRS UMR9187, INSERM U1196, Institut Curie , PSL Research University , Orsay 91405 , France.; CNRS UMR9187, INSERM U1196, Université Paris Sud , Université Paris Saclay , Orsay 91405 , France., Fessl T; Faculty of Science , University of South Bohemia , Ceske Budejovice CZ-370 05 , Czech Republic., Hänsel-Hertsch R; Cancer Research UK Cambridge Institute , University of Cambridge , Cambridge CB2 0RE , United Kingdom., Mergny JL; CNRS UMR9187, INSERM U1196, Institut Curie , PSL Research University , Orsay 91405 , France.; CNRS UMR9187, INSERM U1196, Université Paris Sud , Université Paris Saclay , Orsay 91405 , France.; Institute of Biophysics , v.v.i., ASCR, Brno 62500 , Czech Republic., Foldynova-Trantirkova S; Institute of Biophysics , v.v.i., ASCR, Brno 62500 , Czech Republic., Trantirek L; Central European Institute of Technology, Masaryk University , Brno 62500 , Czech Republic.; Institute of Biophysics , v.v.i., ASCR, Brno 62500 , Czech Republic. |
| المصدر: | Journal of the American Chemical Society [J Am Chem Soc] 2019 Aug 28; Vol. 141 (34), pp. 13281-13285. Date of Electronic Publication: 2019 Aug 14. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 7503056 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-5126 (Electronic) Linking ISSN: 00027863 NLM ISO Abbreviation: J Am Chem Soc Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Washington, DC : American Chemical Society Original Publication: Easton, Pa. [etc.] |
| مواضيع طبية MeSH: | Anti-Infective Agents/*pharmacology , DNA/*metabolism , Naphthalenes/*pharmacology , Netropsin/*pharmacology, Anti-Infective Agents/chemistry ; Base Pairing/drug effects ; Binding Sites/drug effects ; Cell Line ; Cell Survival/drug effects ; DNA/chemistry ; Drug Discovery ; Humans ; Ligands ; Naphthalenes/chemistry ; Netropsin/chemistry ; Nuclear Magnetic Resonance, Biomolecular/methods ; Nucleic Acid Conformation/drug effects |
| مستخلص: | Studies on DNA-ligand interactions in the cellular environment are problematic due to the lack of suitable biophysical tools. To address this need, we developed an in-cell NMR-based approach for monitoring DNA-ligand interactions inside the nuclei of living human cells. Our method relies on the acquisition of NMR data from cells electroporated with preformed DNA-ligand complexes. The impact of the intracellular environment on the integrity of the complexes is assessed based on in-cell NMR signals from unbound and ligand-bound forms of a given DNA target. This technique was tested on complexes of two model DNA fragments and four ligands, namely, a representative DNA minor-groove binder (netropsin) and ligands binding DNA base-pairing defects (naphthalenophanes). In the latter case, we demonstrate that two of the three in vitro -validated ligands retain their ability to form stable interactions with their model target DNA in cellulo , whereas the third one loses this ability due to off-target interactions with genomic DNA and cellular metabolites. Collectively, our data suggest that direct evaluation of the behavior of drug-like molecules in the intracellular environment provides important insights into the development of DNA-binding ligands with desirable biological activity and minimal side effects resulting from off-target binding. |
| المشرفين على المادة: | 0 (Anti-Infective Agents) 0 (Ligands) 0 (Naphthalenes) 64B3O0RD7N (Netropsin) 9007-49-2 (DNA) |
| تواريخ الأحداث: | Date Created: 20190810 Date Completed: 20200930 Latest Revision: 20200930 |
| رمز التحديث: | 20231215 |
| DOI: | 10.1021/jacs.9b03031 |
| PMID: | 31394899 |
| قاعدة البيانات: | MEDLINE |
Find this issue from the American Chemical Society | تدمد: | 1520-5126 |
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| DOI: | 10.1021/jacs.9b03031 |