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.

ARNA Laboratory Université de Bordeaux Inserm U1212 CNRS UMR5320 Institut Européen de Chimie Biologie 2 Rue Robert Escarpit 33607 Pessac France

CNRS 5290 IRD 224 University of Montpellier INSERM 34394 Montpellier France

Department of Biochemistry and Molecular Pharmacology Instituto de Parasitología y Biomedicina CSIC PTS Granada Avda del Conocimiento 17 18016 Armilla Granada Spain

Department of Chemistry University of Pavia Via Taramelli 10 27100 Pavia Italy

Dynamique des Interactions Membranaires Normales et Pathologiques CNRS UMR 5235 Université de Montpellier 34095 Montpellier France

Institute of Biophysics AS CR v v i Kralovopolska 135 612 65 Brno Czech Republic

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Design, synthesis, and antiprotozoal evaluation of new 2,4-bis[(substituted-aminomethyl)phenyl]quinoline, 1,3-bis[(substituted-aminomethyl)phenyl]isoquinoline and 2,4-bis[(substituted-aminomethyl)phenyl]quinazoline derivatives

Genome wide distribution of G-quadruplexes and their impact on gene expression in malaria parasites

Mapping and characterization of G-quadruplexes in the genome of the social amoeba Dictyostelium discoideum

The Presence and Localization of G-Quadruplex Forming Sequences in the Domain of Bacteria

More is not always better: finding the right trade-off between affinity and selectivity of a G-quadruplex ligand