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; Toyin Famodimu, M.; Smargiasso, Nicolas; Damblon, Christian; Horrocks, Paul; Merrick, Catherine J.

doi:10.1128/AAC.01828-17

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.

2018 • In Antimicrobial Agents and Chemotherapy, 62 (3)

Peer Reviewed verified by ORBi

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https://hdl.handle.net/2268/247664

DOI
10.1128/AAC.01828-17

PubMed
29311059

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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 :

Issue :

Peer reviewed :

Peer Reviewed verified by ORBi

Funders :

MRC - Medical Research Council
Jean Shanks Foundation

Funding number :

Nigerian Tertiary Education Trust Fund

Available on ORBi :

since 23 May 2020

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