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G-Quadruplex Identification in the Genome of Protozoan Parasites Points to Naphthalene Diimide Ligands as New Antiparasitic Agents
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SYSNO ASEP 0488390 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title G-Quadruplex Identification in the Genome of Protozoan Parasites Points to Naphthalene Diimide Ligands as New Antiparasitic Agents Author(s) Belmonte-Reche, E. (ES)
Martínez-García, M. (ES)
Guédin, A. (FR)
Zuffo, M. (IT)
Arevalo-Ruiz, M. (ES)
Doria, F. (IT)
Campos-Salinas, J. (ES)
Maynadier, M. (FR)
Lopez-Rubio, J.J. (FR)
Freccero, M. (IT)
Mergny, Jean-Louis (BFU-R) ORCID, RID
Maria Perez-Victoria, J. (ES)
Carlos Morales, J. (ES)Number of authors 13 Source Title Journal of Medicinal Chemistry. - : American Chemical Society - ISSN 0022-2623
Roč. 61, č. 3 (2018), s. 1231-1240Number of pages 10 s. Publication form Print - P Language eng - English Country US - United States Keywords terminal repeat promoter ; plasmodium-falciparum Subject RIV CE - Biochemistry OECD category Biochemistry and molecular biology R&D Projects EF15_003/0000477 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Institutional support BFU-R - RVO:68081707 UT WOS 000425063400041 DOI 10.1021/acs.jmedchem.7b01672 Annotation G-quadruplexes (G4) are DNA secondary structures that take part in the regulation of gene expression. Putative G4 forming sequences (PQS) have been reported in mammals, yeast, bacteria, and viruses. Here, we present PQS searches on the genomes of T. brucei, L. major, and P. falciparum. We found telomeric sequences and new PQS motifs. Biophysical experiments showed that EBR1, a 29 nucleotide long highly repeated PQS in T. brucei, forms a stable G4 structure. G4 ligands based on carbohydrate conjugated naphthalene diimides (carb-NDIs) that bind G4's including hTel could bind EBR1 with selectivity versus dsDNA. These ligands showed important antiparasitic activity. IC50 values were in the nanomolar range against T. brucei with high selectivity against MRC-5 human cells. Confocal microscopy confirmed these ligands localize in the nucleus and kinetoplast of T. brucei suggesting they can reach their potential G4 targets. Cytotoxicity and zebrafish toxicity studies revealed sugar conjugation reduces intrinsic toxicity of NDIs. Workplace Institute of Biophysics Contact Jana Poláková, polakova@ibp.cz, Tel.: 541 517 244 Year of Publishing 2018
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