2. Academic Validation
  3. G-Quadruplex Identification in the Genome of Protozoan Parasites Points to Naphthalene Diimide Ligands as New Antiparasitic Agents

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

  • J Med Chem. 2018 Feb 8;61(3):1231-1240. doi: 10.1021/acs.jmedchem.7b01672.
Efres Belmonte-Reche 1,  Marta Martínez-García 1,  Aurore Guédin 2,  Michela Zuffo 3,  Matilde Arévalo-Ruiz 1,  Filippo Doria 3,  Jenny Campos-Salinas 1,  Marjorie Maynadier 4,  José Juan López-Rubio 5,  Mauro Freccero 3,  Jean-Louis Mergny 2 6,  José María Pérez-Victoria 1,  Juan Carlos Morales 1
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Pharmacology, Instituto de Parasitología y Biomedicina, CSIC , PTS Granada, Avda. del Conocimiento, 17, 18016 Armilla, Granada, Spain.
  • 2 ARNA Laboratory, Université de Bordeaux, Inserm U1212, CNRS UMR5320, Institut Européen de Chimie Biologie (IECB), 2 Rue Robert Escarpit, 33607 Pessac, France.
  • 3 Department of Chemistry, University of Pavia , Via Taramelli 10, 27100 Pavia, Italy.
  • 4 Dynamique des Interactions Membranaires Normales et Pathologiques, CNRS UMR 5235, Université de Montpellier, 34095 Montpellier, France.
  • 5 CNRS, 5290, IRD 224, University of Montpellier (UMR "MiVEGEC"), INSERM, 34394 Montpellier, France.
  • 6 Institute of Biophysics , AS CR, v.v.i. Kralovopolska 135, 612 65 Brno, Czech Republic.
PMID: 29323491 DOI: 10.1021/acs.jmedchem.7b01672
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.

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