Article (Scientific journals)
G-quadruplex DNA motifs in the malaria parasite plasmodium falciparum and their potential as novel antimalarial drug targets
Harris, Lynne M.; Monsell, Katelyn R.; Noulin, Florian et al.
2018In Antimicrobial Agents and Chemotherapy, 62 (3)
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Keywords :
G-quadruplex; Malaria; Plasmodium falciparum; Quarfloxin; RNA 18S; Article; DNA content; DNA replication; DNA structure; DNA transcription; EC50; RNA processing; RNA translation; Trypanosoma
Abstract :
[en] ABSTRACT 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 vivo 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 Plasmodium 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. falciparum 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 P. falciparum 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 P. falciparum may present a target for development of other new antimalarial drugs. Copyright © 2018 American Society for Microbiology. All Rights Reserved.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Harris, Lynne M.;  Centre for Applied Entomology and Parasitology, Faculty of Natural Sciences, Keele University, Keele, Staffordshire, United Kingdom
Monsell, Katelyn R.;  Centre for Applied Entomology and Parasitology, Faculty of Natural Sciences, Keele University, Keele, Staffordshire, United Kingdom
Noulin, Florian;  Centre for Applied Entomology and Parasitology, Faculty of Natural Sciences, Keele University, Keele, Staffordshire, United Kingdom
Toyin Famodimu, M.;  Centre for Applied Entomology and Parasitology, Faculty of Natural Sciences, Keele University, Keele, Staffordshire, United Kingdom
Smargiasso, Nicolas ;  Université de Liège - ULiège > Département de chimie (sciences) > Laboratoire de spectrométrie de masse (L.S.M.)
Damblon, Christian ;  Université de Liège - ULiège > Département de chimie (sciences) > Chimie biologique structurale
Horrocks, Paul;  Centre for Applied Entomology and Parasitology, Faculty of Natural Sciences, Keele University, Keele, Staffordshire, United Kingdom, Institute for Science and Technology in Medicine, Keele University, Keele, Staffordshire, United Kingdom
Merrick, Catherine J.;  Centre for Applied Entomology and Parasitology, Faculty of Natural Sciences, Keele University, Keele, Staffordshire, United Kingdom
Language :
English
Title :
G-quadruplex DNA motifs in the malaria parasite plasmodium falciparum and their potential as novel antimalarial drug targets
Publication date :
2018
Journal title :
Antimicrobial Agents and Chemotherapy
ISSN :
0066-4804
eISSN :
1098-6596
Publisher :
American Society for Microbiology, United States - District of Columbia
Volume :
62
Issue :
3
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
MRC - Medical Research Council [GB]
Jean Shanks Foundation [GB]
Funding number :
Nigerian Tertiary Education Trust Fund
Available on ORBi :
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