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

0488390 - BFÚ 2018 RIV US eng J - Journal Article
Belmonte-Reche, E. - Martínez-García, M. - Guédin, A. - Zuffo, M. - Arevalo-Ruiz, M. - Doria, F. - Campos-Salinas, J. - Maynadier, M. - Lopez-Rubio, J.J. - Freccero, M. - Mergny, Jean-Louis - Maria Perez-Victoria, J. - Carlos Morales, J.
G-Quadruplex Identification in the Genome of Protozoan Parasites Points to Naphthalene Diimide Ligands as New Antiparasitic Agents.
Journal of Medicinal Chemistry. Roč. 61, č. 3 (2018), s. 1231-1240. ISSN 0022-2623. E-ISSN 1520-4804
R&D Projects: GA MŠMT EF15_003/0000477
Institutional support: RVO:68081707
Keywords : terminal repeat promoter * plasmodium-falciparum
OECD category: Biochemistry and molecular biology
Impact factor: 6.054, year: 2018

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.
Permanent Link: http://hdl.handle.net/11104/0282972