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Journal ArticleDOI

Current perspectives on the mechanism of action of artemisinins

01 Dec 2006-International Journal for Parasitology (Int J Parasitol)-Vol. 36, Iss: 14, pp 1427-1441
TL;DR: Evidence for each mechanism of action attributed to artemisinin includes interference with parasite transport proteins, disruption of parasite mitochondrial function, modulation of host immune function and inhibition of angiogenesis, and the evidence for each is reviewed.
About: This article is published in International Journal for Parasitology.The article was published on 2006-12-01. It has received 298 citations till now. The article focuses on the topics: Artemisinin & Mechanism of action.
Citations
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Journal ArticleDOI
TL;DR: Various strategies based on the Fenton reaction have been employed to enhance hydroxyl radical generation, including nanomaterials selection, modulation of the reaction environment, and external energy fields stimulation, which are discussed systematically in this Minireview.
Abstract: Tailored to the specific tumour microenvironment, which involves acidity and the overproduction of hydrogen peroxide, advanced nanotechnology has been introduced to generate the hydroxyl radical ( OH) primarily for tumour chemodynamic therapy (CDT) through the Fenton and Fenton-like reactions Numerous studies have investigated the enhancement of CDT efficiency, primarily the increase in the amount of OH generated Notably, various strategies based on the Fenton reaction have been employed to enhance OH generation, including nanomaterials selection, modulation of the reaction environment, and external energy fields stimulation, which are discussed systematically in this Minireview Furthermore, the potential challenges and the methods used to facilitate CDT effectiveness are also presented to support this cutting-edge research area

1,190 citations

Journal ArticleDOI
TL;DR: The current knowledge about the mode of action of ACTs, their pharmacological properties and the proposed mechanisms of drug resistance are discussed.
Abstract: Plasmodium falciparum resistance to chloroquine and sulphadoxine-pyrimethamine has led to the recent adoption of artemisinin-based combination therapies (ACTs) as the first line of treatment against malaria. ACTs comprise semisynthetic artemisinin derivatives paired with distinct chemical classes of longer acting drugs. These artemisinins are exceptionally potent against the pathogenic asexual blood stages of Plasmodium parasites and also act on the transmissible sexual stages. These combinations increase the rates of clinical and parasitological cures and decrease the selection pressure for the emergence of antimalarial resistance. This Review article discusses our current knowledge about the mode of action of ACTs, their pharmacological properties and the proposed mechanisms of drug resistance.

475 citations


Cites background from "Current perspectives on the mechani..."

  • ...The mechanisms by which ARTs exert their antimalarial activity remain contentiou...

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Journal ArticleDOI
TL;DR: This safe and cheap drug class that saves lives at risk from malaria can also have important potential in oncology, and recent advances in defining the role of artemisinins are discussed.

312 citations

PatentDOI
12 Dec 2008-Nature
TL;DR: In this article, the crystal structure of a plasma membrane proton pump type ATPase was used for identification of modulators of ATPases as well as uses of such modulators.
Abstract: The present invention relates to a crystal structure of a plasma membrane proton pump type ATPase. The invention further describes method for identification of modulators of ATPases as well as uses of such modulators. Based on the provided three dimensional structure of the ATPase, various method, such as computer implemented methods may be used for identification of modulators, such putative modulators may be further analysed using in vitro and in vivo experiments to confirm there functionality. Several modulator interaction regions are described as target of regulation by ATPase modulators.

298 citations

Journal ArticleDOI
TL;DR: The antiemetic meclizine pretreatment confers cardioprotection and neuroprotection against ischemia-reperfusion injury in murine models andNutrient-sensitized screening may provide a useful framework for understanding gene function and drug action within the context of energy metabolism.
Abstract: Most cells have the inherent capacity to shift their reliance on glycolysis relative to oxidative metabolism, and studies in model systems have shown that targeting such shifts may be useful in treating or preventing a variety of diseases ranging from cancer to ischemic injury. However, we currently have a limited number of mechanistically distinct classes of drugs that alter the relative activities of these two pathways. We screen for such compounds by scoring the ability of >3,500 small molecules to selectively impair growth and viability of human fibroblasts in media containing either galactose or glucose as the sole sugar source. We identify several clinically used drugs never linked to energy metabolism, including the antiemetic meclizine, which attenuates mitochondrial respiration through a mechanism distinct from that of canonical inhibitors. We further show that meclizine pretreatment confers cardioprotection and neuroprotection against ischemia-reperfusion injury in murine models. Nutrient-sensitized screening may provide a useful framework for understanding gene function and drug action within the context of energy metabolism.

287 citations

References
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Journal ArticleDOI
22 Nov 1999-Oncogene
TL;DR: It is argued that NF-κB functions more generally as a central regulator of stress responses and pairing stress responsiveness and anti-apoptotic pathways through the use of a common transcription factor may result in increased cell survival following stress insults.
Abstract: Sixteen years have passed since the description of the nuclear factor-кB (NF-кB) as a regulator of к light-chain gene expression in murine B lymphocytes (Sen & Baltimore, 1986a) During that time, over 4,000 publications have appeared, characterizing the family of Rel/NF-кB transcription factors involved in the control of a large number of normal and pathological cellular processes The physiological functions of NF-кB proteins include immunological and inflammatory responses, developmental processes, cellular growth and modulating effects on apoptosis In addition, these factors are activated in a number of diseases, including cancer, arthritis, acute and chronic inflammatory states, asthma, as well as neurodegenerative and heart diseases

3,728 citations

Journal ArticleDOI
13 Apr 2006-Nature
TL;DR: The engineering of Saccharomyces cerevisiae to produce high titres (up to 100 mg l-1) of artemisinic acid using an engineered mevalonate pathway, amorphadiene synthase, and a novel cytochrome P450 monooxygenase from A. annua that performs a three-step oxidation of amorpha-4,11-diene to art Artemisinic acid.
Abstract: Drug-resistant strains of the malaria parasite are widespread, and as a result mortality due to malaria has increased significantly in recent years. Artemisinin, isolated from the herb Artemisia annua (sweet wormwood), is one drug that shows a high efficacy in killing multi-resistant strains of the parasite. The drug is extremely expensive, and high demand has led to a shortage of artemisinin, available only by extraction from the plant source. Ro et al. now report the development of a yeast strain engineered to carry a cytochrome P450 monooxygenase from A. annua that can produce the drug precursor, artemisinic acid. Artemisinin can be synthesized from this precursor. If the efficiency of this process can be improved, this engineered yeast strain has the potential to alleviate the drug shortage. Through the bio-engineering of Saccharomyces cerevisiae high titres of artemisinic acid were produced using a novel cytochrome P450 monooxygenase. Optimization of this process on an industrial scale may significantly reduce the cost of artemisinin, which could then be used to combat malaria in resource-poor settings. Malaria is a global health problem that threatens 300–500 million people and kills more than one million people annually1. Disease control is hampered by the occurrence of multi-drug-resistant strains of the malaria parasite Plasmodium falciparum2,3. Synthetic antimalarial drugs and malarial vaccines are currently being developed, but their efficacy against malaria awaits rigorous clinical testing4,5. Artemisinin, a sesquiterpene lactone endoperoxide extracted from Artemisia annua L (family Asteraceae; commonly known as sweet wormwood), is highly effective against multi-drug-resistant Plasmodium spp., but is in short supply and unaffordable to most malaria sufferers6. Although total synthesis of artemisinin is difficult and costly7, the semi-synthesis of artemisinin or any derivative from microbially sourced artemisinic acid, its immediate precursor, could be a cost-effective, environmentally friendly, high-quality and reliable source of artemisinin8,9. Here we report the engineering of Saccharomyces cerevisiae to produce high titres (up to 100 mg l-1) of artemisinic acid using an engineered mevalonate pathway, amorphadiene synthase, and a novel cytochrome P450 monooxygenase (CYP71AV1) from A. annua that performs a three-step oxidation of amorpha-4,11-diene to artemisinic acid. The synthesized artemisinic acid is transported out and retained on the outside of the engineered yeast, meaning that a simple and inexpensive purification process can be used to obtain the desired product. Although the engineered yeast is already capable of producing artemisinic acid at a significantly higher specific productivity than A. annua, yield optimization and industrial scale-up will be required to raise artemisinic acid production to a level high enough to reduce artemisinin combination therapies to significantly below their current prices.

2,598 citations

Journal ArticleDOI
21 Aug 2003-Nature
TL;DR: It is shown that artemisinins, but not quinine or chloroquine, inhibit the SERCA orthologue (PfATP6) of Plasmodium falciparum in Xenopus oocytes with similar potency to thapsigargin (another sesquiterpene lactone and highly specific SERCA inhibitor).
Abstract: Artemisinins are extracted from sweet wormwood (Artemisia annua) and are the most potent antimalarials available1, rapidly killing all asexual stages of Plasmodium falciparum2. Artemisinins are sesquiterpene lactones widely used to treat multidrug-resistant malaria1, a disease that annually claims 1 million lives. Despite extensive clinical and laboratory experience3, 4, 5 their molecular target is not yet identified. Activated artemisinins form adducts with a variety of biological macromolecules, including haem, translationally controlled tumour protein (TCTP) and other higher-molecular-weight proteins6. Here we show that artemisinins, but not quinine or chloroquine, inhibit the SERCA orthologue (PfATP6) of Plasmodium falciparum in Xenopus oocytes with similar potency to thapsigargin (another sesquiterpene lactone and highly specific SERCA inhibitor). As predicted, thapsigargin also antagonizes the parasiticidal activity of artemisinin. Desoxyartemisinin lacks an endoperoxide bridge and is ineffective both as an inhibitor of PfATP6 and as an antimalarial. Chelation of iron by desferrioxamine abrogates the antiparasitic activity of artemisinins and correspondingly attenuates inhibition of PfATP6. Imaging of parasites with BODIPY-thapsigargin labels the cytosolic compartment and is competed by artemisinin. Fluorescent artemisinin labels parasites similarly and irreversibly in an Fe2+-dependent manner. These data provide compelling evidence that artemisinins act by inhibiting PfATP6 outside the food vacuole after activation by iron.

981 citations

Journal ArticleDOI
24 Feb 2000-Nature
TL;DR: Direct proof that mutations in Pgh1 can confer resistance to mefloquine, quinine and halofantrine is provided, which has important implications for the development and efficacy of future antimalarial agents.
Abstract: Throughout the latter half of this century, the development and spread of resistance to most front-line antimalarial compounds used in the prevention and treatment of the most severe form of human malaria has given cause for grave clinical concern. Polymorphisms in pfmdr1, the gene encoding the P-glycoprotein homologue 1 (Pgh1) protein of Plasmodium falciparum, have been linked to chloroquine resistance1; Pgh1 has also been implicated in resistance to mefloquine and halofantrine2,3,4,5. However, conclusive evidence of a direct causal association between pfmdr1 and resistance to these antimalarials has remained elusive, and a single genetic cross has suggested that Pgh1 is not involved in resistance to chloroquine and mefloquine6. Here we provide direct proof that mutations in Pgh1 can confer resistance to mefloquine, quinine and halofantrine. The same mutations influence parasite resistance towards chloroquine in a strain-specific manner and the level of sensitivity to the structurally unrelated compound, artemisinin. This has important implications for the development and efficacy of future antimalarial agents.

848 citations

Journal ArticleDOI
TL;DR: It is shown that increase in copy number of pfmdr1, a gene encoding a parasite transport protein, is the best overall predictor of treatment failure with mefloquine.

794 citations