Plasmodium falciparum:Effect of Chemical Structure on Efficacy and Specificity of Antisense Oligonucleotides against Malariain Vitro

Barker, Robert H.; Metelev, Valeri; Coakley, Aran; Zamecnik, Paul C.

doi:10.1006/expr.1998.4192

Cited by 15 publications

(3 citation statements)

References 28 publications

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“…The genome of the malaria parasite is ~80% AT bp [92] and is substantially different from the human genome; which may provide opportunities to use sequence specific inhibitors to target the parasite"s genome [93]. ASOs have been used in the malaria parasite for various applications [94,95] but with some delivery issues associated with uptake of charged ASOs into the malaria parasite [93] that could possibly be overcome with the use of peptide nucleic acids (PNA), as a potentially more metabolically stable and neutral alternative [96].…”

Section: Antisense Oligonucleotides (Aso)mentioning

confidence: 99%

Resisting resistance: is there a solution for malaria?

Verlinden

Louw

Birkholtz

2016

Expert Opinion on Drug Discovery

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IntroductionCurrently, widely used antimalarial drugs have a limited clinical lifespan due to parasite resistance development. With resistance continuously rising, antimalarial drug discovery requires strategies to decrease the time of delivering a new antimalarial drug while simultaneously increasing the drug"s therapeutic lifespan. Areas coveredLessons learnt from various chemotherapeutic resistance studies in the fields of antibiotic and cancer research offer potentially useful strategies that can be applied to antimalarial drug discovery. In this review we discuss current strategies to circumvent resistance in malaria and alternatives that could be employed. Expert opinionWe have been "beating back" the malaria parasite with novel drugs for the past 49 years but the constant rise in antimalarial drug resistance is forcing the drug discovery community to explore alternative strategies. Avant-garde anti-resistance strategies from alternative fields may assist our endeavors to manage, control and prevent antimalarial drug resistance to progress beyond beating the resistant parasite back, to stopping it dead in its tracks. Here we investigate the 2 development of strategies that are able to either overwhelm or outwit the parasite in its attempts to develop resistance. Article Highlights box In most instances the malaria parasite develops drug resistance at a faster rate than a novel antimalarial drug can be developed. For antimalarial drug discovery to remain sustainable, the clinical lifespan of an antimalarial drug must as least exceed the time taken to develop the drug. Currently, antimalarial drug resistance is being controlled through the development of novel drugs, which are combined with an appropriate drug partner into a combination therapy. Polypharmacology (multitargeting) may be able to speed up the delivery of a novel antimalarial drug while simultaneously increasing the clinical lifespan of the drug. Unexplored targets such as the virulence potential, hijacked host factors and stress factors may deliver drugs that can effectively resist resistance. Other post-resistance strategies such as molecular decoys and chemogenomics may also prove valuable in curbing resistance.

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Section: Antisense Oligonucleotides (Aso)mentioning

confidence: 99%

Resisting resistance: is there a solution for malaria?

Verlinden

Louw

Birkholtz

2016

Expert Opinion on Drug Discovery

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“…Using metabolically stable phosphothioated (PS) ASO [7], [8], [9], [10], sequence-specific down-regulation of several endogenous genes was shown at concentrations of ASO typically in the range of 0.1 to 0.5 µM. However, non-specific growth inhibition was observed at higher ASO concentrations.…”

Section: Introductionmentioning

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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“…Recent studies have explored the suitability of using nucleic acids as antimalarial agents. Promising results have been obtained with both antisense DNA (Barker et al 1996(Barker et al , 1998Katrib et al 1997) and synthetic ribozymes ; M.V.C. Flores, D. Atkins, T.S.…”

Section: Introductionmentioning

confidence: 99%

Antimalarial antisense activity of hexitol nucleic acids

Flores¹,

Atkins

Stewart³

et al. 1999

Parasitology Research

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Antisense oligonucleotides and ribozymes have shown promise both as antimalarial agents and as tools for identifying genes vital for parasite survival. This task is urgent due to the ineffectiveness of current drug regimes on the most virulent human malarial parasite, Plasmodium falciparum. The development of new ways to modify and/or protect conventional phosphodiester oligonucleotides to improve nuclease resistance is also important. We assessed the effect of antisense oligonucleotides containing phosphorylated anhydrohexitols in suppressing the growth of P. falciparum in culture. The modified oligonucleotides were able to inhibit parasite growth in a sequence-specific manner, but not as well as the phosphorothioated antisense oligonucleotides, which are effective antimalarials at submicromolar concentrations. Two reasons are suggested: the absence of RNase H activation and differences in membrane transport.

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Plasmodium falciparum:Effect of Chemical Structure on Efficacy and Specificity of Antisense Oligonucleotides against Malariain Vitro

Cited by 15 publications

References 28 publications

Resisting resistance: is there a solution for malaria?

Resisting resistance: is there a solution for malaria?

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

Antimalarial antisense activity of hexitol nucleic acids

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