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

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 occur in the DNA of human cells and other systems, where they play...

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Bibliographic Details
Published in:Antimicrobial agents and chemotherapy 2018-03, Vol.62 (3)
Main Authors: Harris, Lynne M, Monsell, Katelyn R, Noulin, Florian, Famodimu, M Toyin, Smargiasso, Nicolas, Damblon, Christian, Horrocks, Paul, Merrick, Catherine J
Format: Article
Language:English
Subjects:
Antimalarials
Antimalarials - pharmacology
Biochemistry, biophysics & molecular biology
Biochimie, biophysique & biologie moléculaire
DNA content
DNA replication
DNA structure
DNA transcription
EC50
Experimental Therapeutics
G-quadruplex
G-Quadruplexes
G-Quadruplexes - drug effects
Humans
Life sciences
Malaria
Malaria, Falciparum - microbiology
Plasmodium falciparum
Plasmodium falciparum - drug effects
Plasmodium falciparum - genetics
Quarfloxin
RNA 18S
RNA processing
RNA translation
Sciences du vivant
Trypanosoma
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Summary: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 occur in 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 parasite , 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, parasites 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 in but 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 in may present a target for development of other new antimalarial drugs.
ISSN:0066-4804
1098-6596
1098-6596
DOI:10.1128/AAC.01828-17