Inhibition of malarial topoisomerase II in Plasmodium falciparum by antisense nanoparticles

Föger, Florian; Noonpakdee, Wilai; Loretz, Brigitta; Joojuntr, Songwut; Salvenmoser, Willi; Thaler, Marlene; Bernkop‐Schnürch, Andreas

doi:10.1016/j.ijpharm.2006.03.034

Cited by 57 publications

(29 citation statements)

References 29 publications

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“…This suggestion agrees with the observed low efficiency of the RNAi effect and with the fact that mature erythrocytes do not produce RNAi machinery de novo and thus are expected to have only low levels of RNAi components. Alternatively, it is possible that the antisense strand of siRNA has inhibited PfPIG-B mRNA translation as suggested by previous studies [24,26,27]. Regardless of the mechanism involved, our results indicate that the PfPIG-B gene studied here is functional and encodes for α (1-2)mannosyltransferase-III of P. falciparum GPI biosynthesis.…”

Section: Discussionsupporting

confidence: 67%

Plasmodium falciparum GPI mannosyltransferase-III has novel signature sequence and is functional

Basagoudanavar

Feng

Gowda

et al. 2007

Biochemical and Biophysical Research Communications

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The glycosylphosphatidylinositol (GPI) anchors of Plasmodium falciparum are indispensable for parasite survival since merozoite surface proteins-1, -2, -4, -5 and -10 crucial for erythrocyte invasion are GPI-anchored. Therefore, the GPI biosynthetic pathway can offer potential targets for novel antimalarial drugs. Here, we characterized the putative P. falciparum PIG-B gene (PfPIGB) that encodes mannosyltransferase-III of GPI biosynthesis. PfPIGB mRNA is transcribed in a developmental stage specific manner. A protein corresponding to the expected size of PfPIG-B is expressed by the parasite and is localized in the endoplasmic reticulum. Treatment of parasites with PfPIG-B specific siRNA caused reduced GPI synthesis, affecting the PIG-B specific GPI intermediate. These data demonstrate that PfPIG-B is functional and encodes for mannosyltransferase-III of the parasite GPI biosynthesis. The parasite PfPIG-B is novel in that its signature sequence HKEHKI is unique and is only partially conserved compared to HKEXRF signature motif of mammalian PIG-B enzymes. KeywordsPlasmodium falciparum; glycosylphosphatidylinositol anchors; biosynthesis; mannosyltransferase-III; characterization Malaria caused by Plasmodium falciparum is a major health problem in many countries. About 40% of the global population is at risk to malaria, and in sub-Saharan Africa, millions of deaths, mostly among children less than 5 years old, occur every year [1]. The death toll due to malaria has been rapidly increasing because of drug resistance. Development of novel drugs targeting the essential metabolic pathways of the parasite and therapeutics/vaccine that prevent the infection and/or illness are urgently needed. In this context, glycosylphosphatidylinositol (GPI) biosynthetic pathway can offer important targets [2].The GPIs of all organisms have a conserved glycan core, Manα1-2Manα1-6Manα1-4GlcNα1, covalently linked to myo-inositol of phosphatidylinositol (PI) at O-6 [3]. The mannose-3 of the glycan core is invariably substituted at O-6 with EtN-P, which is used for membrane anchoring of proteins through amide bond formation with the -COOH of the protein C-termini. GPIs from different organisms vary in the PI moiety in having acylated or nonacylated myo-inositol, and diacylglycerols, monoacylglycerols, alkyl/acylglycerols or ceramide [3]. In the case of P. falciparum GPIs, the conserved glycan core is substituted with an additional Man at O-2 of the third Man, and the PI comprised of diacylglycerol and O-2-acylated inositol moieties, both with variable fatty acids [4]. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptThe biosynthesis of GPIs occurs in the ER by the sequential addition of sugars to the PI by a coordinated action of glycosyltransferases, N-deacetylase, inositol acylase, EtN-P transferase, and several accessory proteins [5]. The preassembled GPIs are transferred enbloc to the Ctermini of proteins that have GPI attachment signal sequence. In animals, hundreds of proteins including cell surface re...

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Section: Discussionsupporting

confidence: 67%

Plasmodium falciparum GPI mannosyltransferase-III has novel signature sequence and is functional

Basagoudanavar

Feng

Gowda

et al. 2007

Biochemical and Biophysical Research Communications

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“…Leonardi et al (2009) studied also the effect of benznidazole CS microparticles in treatment of Chaga's disease. In order to improve stability and to increase intracellular penetration of oligodeoxynucleotides (ODNs) as anti malaria agent, Föger et al (2006) combined it with the biodegradable polymer CS to form solid nanoparticles. It exhibited a significantly stronger inhibitory effect (approximately 74% inhibition) than free ODNs.…”

Section: Discussionmentioning

confidence: 99%

“…They offer a new pharmacological tool for the treatment of Leishmania, P. falciparum, and Cryptosporidia. They reduced the doses required and lowering toxic side effects of the used drugs (Pujals et al 2008;(Föger et al 2006);Kayser 2001). They were used also for improving the efficacy and bioavailability of Cur in treatment of Plasmodium berghei-infected mice (Feroz and Santosh 2010).…”

Section: Introductionmentioning

confidence: 99%

Validity of silver, chitosan, and curcumin nanoparticles as anti-Giardia agents

2012

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This study was carried out to evaluate the anti parasitic potential of silver, chitosan, and curcumin nanoparticles as anti-Giardia agents. Non-treated infected control rats were inoculated with Giardia lamblia cysts in a dose of 2 × 10(5) cysts/rat. Experimental group was infected then treated with curcumin, curcumin nanoparticles, chitosan, chitosan nanoparticles, and silver nanoparticles as single or combined therapy. The number of Giardia cysts in stools and trophozoites in intestinal sections were detected. Toxicity of nanoparticles was evaluated by comparing hematological and histopathological parameters of the normal control group and treated non-infected control group. The amount of silver was also measured in the liver, kidney, small intestine, lung, and brain of rats treated with silver nanoparticles. The number of the parasites in stool and small intestinal sections decreased in treated infected rats compared with infected non-treated ones. The effect in the single therapy was better with nanoparticles, and the best effect was detected in nano-silver. The combined therapy gave better results than single. Combination between nanoparticles was better than the combination of nano-forms and native chitosan and curcumin. The best effect was detected in combinations of nano-silver and nano-chitosan but with no full eradication. In conclusion, the highest effect and complete cure was gained by combining the three nano-forms. The parasite was successfully eradicated from stool and intestine. None of the treatments exhibited any toxicity. Accumulated silver in different organs was within the safe limits.

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“…However, antisense-based therapy was thus far limited by the rapid degradation of the nucleotides in vivo as well as their inefficient delivery across cell membranes and their inability to reach their target mRNAs due to their hydrophilic character and high molecular structure [33]. In order to improve stability and to increase intracellular penetration, Föger and co-workers [34] formulated topoisomerase II ASO into biocompatible chitosan based nanoparticles (NPs). They showed that using these NPs they can increase growth inhibition without increasing the hemolytic activity of the ASO on RBCs.…”

Section: Discussionmentioning

confidence: 99%

Use of Peptide Nucleic Acids to Manipulate Gene Expression in the Malaria Parasite Plasmodium falciparum

Kolevzon

Nasereddin²,

Naik

et al. 2014

PLoS ONE

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One of the major concerns in treating malaria by conventional small drug molecules is the rapid emergence of drug resistance. Specific silencing of essential genes by antisense oliogomers has been proposed as an alternative approach that may result in antimalarial activity which is not associated with drug resistance. In addition, such an approach could be an important biological tool for studying many genes' function by reverse genetics. Here we present a novel methodology of using peptide nucleic acids (PNAs) as a useful tool for gene silencing in Plasmodium falciparum. PNAs, designed as specific antisense molecules, were conjugated to a cell penetrating peptide (CPP); namely, octa-D-lysine via the C-terminus, to allow facile delivery through cell membranes. PNAs added to P. falciparum cultures were found exclusively in infected erythrocytes and were eventually localized in nuclei of the parasites at all stages of intra erythrocytic development. We show that these PNAs specifically down regulated both a stably expressed transgene as well as an endogenous essential gene, which significantly reduced parasites' viability. This study paves the way for a simple approach to silence a variety of P. falciparum genes as means of deciphering their function and potentially to develop highly specific and potent antimalarial agents.

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Inhibition of malarial topoisomerase II in Plasmodium falciparum by antisense nanoparticles

Cited by 57 publications

References 29 publications

Plasmodium falciparum GPI mannosyltransferase-III has novel signature sequence and is functional

Plasmodium falciparum GPI mannosyltransferase-III has novel signature sequence and is functional

Validity of silver, chitosan, and curcumin nanoparticles as anti-Giardia agents

Use of Peptide Nucleic Acids to Manipulate Gene Expression in the Malaria Parasite Plasmodium falciparum

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