Accéder directement au contenu Accéder directement à la navigation
Article dans une revue

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

Abstract : 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.
Liste complète des métadonnées

https://hal.umontpellier.fr/hal-02863564
Contributeur : Hal Mivegec <>
Soumis le : mercredi 10 juin 2020 - 12:33:28
Dernière modification le : lundi 1 mars 2021 - 16:26:03

Lien texte intégral

Identifiants

Collections

Citation

Efres Belmonte-Reche, Marta Martínez-García, Aurore Guédin, Michela Zuffo, Matilde Arévalo-Ruiz, et al.. G-Quadruplex Identification in the Genome of Protozoan Parasites Points to Naphthalene Diimide Ligands as New Antiparasitic Agents. Journal of Medicinal Chemistry, American Chemical Society, 2018, 61 (3), pp.1231-1240. ⟨10.1021/acs.jmedchem.7b01672⟩. ⟨hal-02863564⟩

Partager

Métriques

Consultations de la notice

37