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G-Quadruplex Identification in the Genome of Protozoan Parasites Points to Naphthalene Diimide Ligands as New Antiparasitic Agents

[Image: see text] 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. falcipa...

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Autores principales: Belmonte-Reche, Efres, Martínez-García, Marta, Guédin, Aurore, Zuffo, Michela, Arévalo-Ruiz, Matilde, Doria, Filippo, Campos-Salinas, Jenny, Maynadier, Marjorie, López-Rubio, José Juan, Freccero, Mauro, Mergny, Jean-Louis, Pérez-Victoria, José María, Morales, Juan Carlos
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2018
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6148440/
https://www.ncbi.nlm.nih.gov/pubmed/29323491
http://dx.doi.org/10.1021/acs.jmedchem.7b01672
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author Belmonte-Reche, Efres
Martínez-García, Marta
Guédin, Aurore
Zuffo, Michela
Arévalo-Ruiz, Matilde
Doria, Filippo
Campos-Salinas, Jenny
Maynadier, Marjorie
López-Rubio, José Juan
Freccero, Mauro
Mergny, Jean-Louis
Pérez-Victoria, José María
Morales, Juan Carlos
author_facet Belmonte-Reche, Efres
Martínez-García, Marta
Guédin, Aurore
Zuffo, Michela
Arévalo-Ruiz, Matilde
Doria, Filippo
Campos-Salinas, Jenny
Maynadier, Marjorie
López-Rubio, José Juan
Freccero, Mauro
Mergny, Jean-Louis
Pérez-Victoria, José María
Morales, Juan Carlos
author_sort Belmonte-Reche, Efres
collection PubMed
description [Image: see text] 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. IC(50) 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.
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spelling pubmed-61484402018-09-24 G-Quadruplex Identification in the Genome of Protozoan Parasites Points to Naphthalene Diimide Ligands as New Antiparasitic Agents Belmonte-Reche, Efres Martínez-García, Marta Guédin, Aurore Zuffo, Michela Arévalo-Ruiz, Matilde Doria, Filippo Campos-Salinas, Jenny Maynadier, Marjorie López-Rubio, José Juan Freccero, Mauro Mergny, Jean-Louis Pérez-Victoria, José María Morales, Juan Carlos J Med Chem [Image: see text] 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. IC(50) 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. American Chemical Society 2018-01-11 2018-02-08 /pmc/articles/PMC6148440/ /pubmed/29323491 http://dx.doi.org/10.1021/acs.jmedchem.7b01672 Text en Copyright © 2018 American Chemical Society This is an open access article published under an ACS AuthorChoice License (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) , which permits copying and redistribution of the article or any adaptations for non-commercial purposes.
spellingShingle Belmonte-Reche, Efres
Martínez-García, Marta
Guédin, Aurore
Zuffo, Michela
Arévalo-Ruiz, Matilde
Doria, Filippo
Campos-Salinas, Jenny
Maynadier, Marjorie
López-Rubio, José Juan
Freccero, Mauro
Mergny, Jean-Louis
Pérez-Victoria, José María
Morales, Juan Carlos
G-Quadruplex Identification in the Genome of Protozoan Parasites Points to Naphthalene Diimide Ligands as New Antiparasitic Agents
title G-Quadruplex Identification in the Genome of Protozoan Parasites Points to Naphthalene Diimide Ligands as New Antiparasitic Agents
title_full G-Quadruplex Identification in the Genome of Protozoan Parasites Points to Naphthalene Diimide Ligands as New Antiparasitic Agents
title_fullStr G-Quadruplex Identification in the Genome of Protozoan Parasites Points to Naphthalene Diimide Ligands as New Antiparasitic Agents
title_full_unstemmed G-Quadruplex Identification in the Genome of Protozoan Parasites Points to Naphthalene Diimide Ligands as New Antiparasitic Agents
title_short G-Quadruplex Identification in the Genome of Protozoan Parasites Points to Naphthalene Diimide Ligands as New Antiparasitic Agents
title_sort g-quadruplex identification in the genome of protozoan parasites points to naphthalene diimide ligands as new antiparasitic agents
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6148440/
https://www.ncbi.nlm.nih.gov/pubmed/29323491
http://dx.doi.org/10.1021/acs.jmedchem.7b01672
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