G-Quadruplex ligands: Potent inhibitors of telomerase activity and cell proliferation in Plasmodium falciparum

Calvo, Eliana; Wasserman, Moisés

doi:10.1016/j.molbiopara.2016.05.009

Cited by 28 publications

(28 citation statements)

References 38 publications

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“…This translates to only one PQS per ϳ300 kb of the nontelomeric P. falciparum genome, compared to an average of one PQS per kb in the human genome (7). Several hundred PQSs were also found in the P. falciparum telomeres, which have the repeat sequence GGGTT(T/C)A and are inherently able to form G-quadruplexes (11,12). Predicting the expected PQS density of a given genome is not straightforward due to variable genome compositions and biased base dyad frequencies, but under the simplest predictive algorithm (a Bernoulli stream of random bases at 81% A/T), a genome with the size and composition of the P. falciparum genome contains no PQSs at all (5); therefore, the maintenance of PQSs in specific genomic regions is likely to be biologically functional.…”

mentioning

confidence: 99%

G-Quadruplex DNA Motifs in the Malaria Parasite Plasmodium falciparum and Their Potential as Novel Antimalarial Drug Targets

Harris

Monsell

Noulin

et al. 2018

Antimicrob Agents Chemother

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G-quadruplexes are DNA or RNA secondary structures that can be formed from guanine-rich nucleic acids. These four-stranded structures, composed of stacked quartets of guanine bases, can be highly stable and have been demonstrated to occurin vivoin the DNA of human cells and other systems, where they play important biological roles, influencing processes such as telomere maintenance, DNA replication and transcription, or, in the case of RNA G-quadruplexes, RNA translation and processing. We report for the first time that DNA G-quadruplexes can be detected in the nuclei of the malaria parasitePlasmodium falciparum, which has one of the most A/T-biased genomes sequenced and therefore possesses few guanine-rich sequences with the potential to form G-quadruplexes. We show that despite this paucity of putative G-quadruplex-forming sequences,P. falciparumparasites are sensitive to several G-quadruplex-stabilizing drugs, including quarfloxin, which previously reached phase 2 clinical trials as an anticancer drug. Quarfloxin has a rapid initial rate of kill and is active against ring stages as well as replicative stages of intraerythrocytic development. We show that several G-quadruplex-stabilizing drugs, including quarfloxin, can suppress the transcription of a G-quadruplex-containing reporter gene inP. falciparumbut that quarfloxin does not appear to disrupt the transcription of rRNAs, which was proposed as its mode of action in both human cells and trypanosomes. These data suggest that quarfloxin has potential for repositioning as an antimalarial with a novel mode of action. Furthermore, G-quadruplex biology inP. falciparummay present a target for development of other new antimalarial drugs.

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confidence: 99%

G-Quadruplex DNA Motifs in the Malaria Parasite Plasmodium falciparum and Their Potential as Novel Antimalarial Drug Targets

Harris

Monsell

Noulin

et al. 2018

Antimicrob Agents Chemother

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“…Of note, there is little to no overlap of PfAP2Tel peaks and Gquadruplex sequences identified in the P. falciparum genome (Calvo & Wasserman, 2016; data not shown); such sequences are thought to increase recombination events near chromosome ends, promoting antigenic variation and improving the ability of the parasite to evade the host immune response (Calvo & Wasserman, 2016).…”

Section: Pfap2tel Is a Nuclear Protein That Co-localises With Telommentioning

confidence: 99%

“…(SupplementaryFigure S4) and the role of PfAP2Tel in regulating these genes remains to be explored.Of note, there is little to no overlap of PfAP2Tel peaks and Gquadruplex sequences identified in the P. falciparum genome(Calvo & Wasserman, 2016; data not shown); such sequences are thought to increase recombination events near chromosome ends, promoting antigenic variation and improving the ability of the parasite to evade the host immune response(Calvo & Wasserman, 2016). These 544 genes belong to families such as PfEMP1 (encoded by var), rifin, stevor, and Pfmc-2TM, genes encoding exported proteins and conserved proteins of unknown function, and so forth.…”

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confidence: 99%

PfAP2Tel, harbouring a non-canonical DNA-binding AP2 domain, binds toPlasmodium falciparumtelomeres

Sierra-Miranda¹,

Vembar

Delgadillo³

et al. 2017

Cellular Microbiology

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The telomeres of the malaria parasite Plasmodium falciparum are essential not only for chromosome end maintenance during blood stage development in humans but also to generate genetic diversity by facilitating homologous recombination of subtelomeric, multigene virulence families such as var and rifin. However, other than the telomerase PfTERT, proteins that act at P. falciparum telomeres are poorly characterised. To isolate components that bind to telomeres, we performed oligonucleotide pulldowns and electromobility shift assays with a telomeric DNA probe and identified a non-canonical member of the ApiAP2 family of transcription factors, PfAP2Tel (encoded by PF3D7_0622900), as a component of the P. falciparum telomere-binding protein complex. PfAP2Tel is expressed throughout the intra-erythrocytic life cycle and localises to the nuclear periphery, co-localising with telomeric clusters. Furthermore, EMSAs using the recombinant protein demonstrated direct binding of PfAP2Tel to telomeric repeats in vitro, while genome-wide chromatin immunoprecipitation followed by next generation sequencing corroborated the high specificity of this protein to telomeric ends of all 14 chromosomes in vivo. Taken together, our data describe a novel function for ApiAP2 proteins at chromosome ends and open new avenues to study the molecular machinery that regulates telomere function in P. falciparum.

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“…In addition, the in vitro cytotoxicity of our new bis[(substitutedaminomethyl)phenyl]quinoline-like derivatives was assessed in human HepG2 cells, and an index of selectivity, the ratio of cytotoxic to antiparasitic activity, was determined for each derivative. The telomeres of the different protozoa could constitute attractive drug targets [36][37][38][39] and telomerase activity is detected in gametocytes and during the transition to the erythrocytic stage of P. falciparum 40 . The telomeric 3 0 G-overhang region of P. falciparum is a repetition of degenerate unit 5 0 -GGGTTYA-3 0 (where Y could be T or C) 41 which can fold into intramolecular G-quadruplex 42 .…”

Section: Introductionmentioning

confidence: 99%

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

Guillon

Cohen

Boudot

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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G-Quadruplex ligands: Potent inhibitors of telomerase activity and cell proliferation in Plasmodium falciparum

Cited by 28 publications

References 38 publications

G-Quadruplex DNA Motifs in the Malaria Parasite Plasmodium falciparum and Their Potential as Novel Antimalarial Drug Targets

G-Quadruplex DNA Motifs in the Malaria Parasite Plasmodium falciparum and Their Potential as Novel Antimalarial Drug Targets

PfAP2Tel, harbouring a non-canonical DNA-binding AP2 domain, binds toPlasmodium falciparumtelomeres

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

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