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; Famodimu, Mufuliat T.; Smargiasso, Nicolas; Damblon, Christian; Horrocks, Paul; Merrick, Catherine J.

doi:10.1128/aac.01828-17

Cited by 50 publications

(86 citation statements)

References 50 publications

(70 reference statements)

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“…Effect of NMM on infectious agents. NMM has been identified as a potential drug against the malaria parasite [75], the pseudorabies virus [71], and antigenic variation in the gonorrhea bacterium [76]. These effects are directly linked to NMM's ability to induce and stabilize GQ structures, thereby indicating that GQs are viable targets in infectious diseases.…”

Section: Using Nmm To Study Gq Dna In Biological Contextsmentioning

confidence: 99%

N-methyl mesoporphyrin IX as a highly selective light-up probe for G-quadruplex DNA

Yett

Lin

Beseiso

et al. 2019

J. Porphyrins Phthalocyanines

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[Formula: see text]-methyl mesoporphyrin IX (NMM) is a water-soluble, non-symmetric porphyrin with excellent optical properties and unparalleled selectivity for G-quadruplex (GQ) DNA. G-quadruplexes are non-canonical DNA structures formed by guanine-rich sequences. They are implicated in genomic stability, longevity, and cancer. The ability of NMM to selectively recognize GQ structures makes it a valuable scaffold for designing novel GQ binders. In this review, we survey the literature describing the GQ-binding properties of NMM as well as its wide utility in chemistry and biology. We start with the discovery of the GQ-binding properties of NMM and the development of NMM-binding aptamers. We then discuss the optical properties of NMM, focusing on the light-switch effect — high fluorescence of NMM induced upon its binding to GQ DNA. Additionally, we examine the affinity and selectivity of NMM for GQs, as well as its ability to stabilize GQ structures and favor parallel GQ conformations. Furthermore, a portion of the review is dedicated to the applications of NMM-GQ complexes as biosensors for heavy metals, small molecules ([Formula: see text] ATP and pesticides), DNA, and proteins. Finally and importantly, we discuss the utility of NMM as a probe to investigate the roles of GQs in biological processes.

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Section: Using Nmm To Study Gq Dna In Biological Contextsmentioning

confidence: 99%

N-methyl mesoporphyrin IX as a highly selective light-up probe for G-quadruplex DNA

Yett

Lin

Beseiso

et al. 2019

J. Porphyrins Phthalocyanines

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“…G-quadruplex sequences are also evolutionary conserved across different living organisms. They are present in essential genomic loci of Saccharomyces cerevisiae 13,14 , Plasmodium falciparum 15,16 , Neiserria gonorrhea 17 , Mycobacterium tuberculosis 18 , Streptococcus pneumononiae 19 and several viruses 20 . They are also found in the genomes of plants including Arabidopsis thaliana, and Oryza sativa 21,22 .…”

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confidence: 99%

Identification and characterization of two conserved G-quadruplex forming motifs in the Nipah virus genome and their interaction with G-quadruplex specific ligands

Majee

Mishra

Pandya

et al. 2020

Sci Rep

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The G-quadruplex (GQ) motifs are considered as potential drug-target sites for several human pathogenic viruses such as Zika, Hepatitis, Ebola, and Human Herpesviruses. The recent outbreaks of Nipah virus (NiV) in India, the highly fatal emerging zoonotic virus is a potential threat to global health security as no anti-viral drug or vaccine in currently available. Therefore, here in the present study, we sought to assess the ability of the putative G-quadruplex forming sequences in the NiV genome to form G-quadruplex structures and act as targets for anti-viral compounds. Bioinformatics analysis underpinned by various biophysical and biochemical techniques (such as NMR, CD, EMSA, DMS footprinting assay) confirmed the presence of two highly conserved G-quadruplex forming sequences (HGQs) in the G and L genes of NiV. These genes encode the cell attachment glycoprotein and RNAdependent RNA polymerase, respectively and are essential for the virus entry and replication within the host cell. It remains possible that stabilization of these HGQs by the known G-quadruplex binding ligands like TMPyP4 and Braco-19 represents a promising strategy to inhibit the expression of the HGQ harboring genes and thereby stop the viral entry and replication inside the host cell. Accordingly, we report for the first time, that HGQs in Nipah virus genome are targets for G-quadruplex specific ligands; therefore, could serve as potential targets for anti-viral therapy.

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“…Very few Plasmodium sequences have been thus verified, and the two that have were selected a priori by QGRS Mapper. (Notably, neither of them -belonging to the rifin gene PF3D7_0700200 and the var upsB region [15,29] -were found here by G4 Hunter: they presumably fall into the false negative category which is expected to be quite large at a threshold of 1.7.) Here, we experimentally tested three new G4 Hunter motifs, including two with the apparent potential to form only two-quartet rather than three-quartet G4s.…”

Section: Discussionmentioning

confidence: 62%

“…This could potentially allow the var genes to benefit from the recombination-promoting effects of G4s without suffering any interruption of coding-strand transcription, which could impede efficient production of PfEMP1. (We have previously showed that a stabilized coding-strand G4 can inhibit transcription of a rifin reporter gene [29], so the same could be true for G4-encoding var genes.) Coding PQSs -at least amongst the upsB var genes that were analysed in figure 5 -occurred mostly around the middle of var gene sequences, within the second exon that encodes the variable extracellular domain of PfEMP1.…”

Section: Discussionmentioning

confidence: 86%

Conserved associations between G-quadruplex-forming DNA motifs and virulence gene families in malaria parasites

Gage

Merrick

2020

Preprint

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Background: The Plasmodium genus of malaria parasites encodes several families of antigenencoding genes. These genes tend to be hyper-variable, highly recombinogenic and variantly expressed. The best-characterized family is the var genes, exclusively found in the Laveranian subgenus of malaria parasites infecting humans and great apes. Var genes encode major virulence factors involved in immune evasion and the maintenance of chronic infections. In the human parasite P. falciparum, var gene recombination and diversification appear to be promoted by G-quadruplex (G4) DNA motifs, which are strongly associated with var genes in P. falciparum. Here, we investigated how this association might have evolved across Plasmodium species -both Laverania and also more distantly related species which lack vars but encode other, more ancient variant gene families.Results: The association between var genes and G4-forming motifs was conserved across Laverania, spanning ~1 million years of evolutionary time, with suggestive evidence for evolution of the association occurring within this subgenus. In rodent malaria species, G4-forming motifs were somewhat associated with pir genes, but this was not conserved in the Laverania, nor did we find a strong association of these motifs with any gene family in a second outgroup of avian malaria parasites. Secondly, we compared two different G4 prediction algorithms in their performance on extremely A/T-rich Plasmodium genomes, and also compared these predictions with experimental data from G4-seq, a DNA sequencing method for identifying G4-forming motifs. We found a surprising lack of concordance between the two algorithms and also between the algorithms and G4-seq data.Conclusions: G4-forming motifs are uniquely strongly associated with Plasmodium var genes, suggesting a particular role for G4s in recombination and diversification of these genes. Secondly, in the A/T-rich genomes of Plasmodium species, the choice of prediction algorithm may be particularly influential when studying G4s in these important protozoan pathogens. BackgroundMalaria is caused by protozoan Plasmodium parasites: in humans it causes considerable morbidity and is still responsible for almost half a million deaths each year [1]. Most severe cases of human malaria are caused by Plasmodium falciparum, but a further five parasite species can infect humans 3 and there are many more species that infect rodents, birds and other vertebrates. In all vertebrate hosts, the disease involves cyclical infection of erythrocytes by Plasmodium parasites. The infected cells are exposed to circulating immune factors and also to splenic clearance, yet many malarias can lead to both chronic and repeated infections, indicating that the parasites have considerable capacities for immune evasion. These capacities have been linked, in several species, to the variant expression of virulence factors that are exposed on the infected erythrocyte surface and are encoded by highly variable families of variantly-expressed virulence genes.Such gene fa...

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

Cited by 50 publications

References 50 publications

N-methyl mesoporphyrin IX as a highly selective light-up probe for G-quadruplex DNA

N-methyl mesoporphyrin IX as a highly selective light-up probe for G-quadruplex DNA

Identification and characterization of two conserved G-quadruplex forming motifs in the Nipah virus genome and their interaction with G-quadruplex specific ligands

Conserved associations between G-quadruplex-forming DNA motifs and virulence gene families in malaria parasites

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