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Artemisinin

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Arjen M Dondorp – 1st expert on this subject based on the ideXlab platform

  • Artemisinin resistant plasmodium falciparum malaria
    Microbiology spectrum, 2016
    Co-Authors: Rick M Fairhurst, Arjen M Dondorp

    Abstract:

    For more than five decades, Southeast Asia (SEA) has been fertile ground for the emergence of drug-resistant Plasmodium falciparum malaria. After generating parasites resistant to chloroquine, sulfadoxine, pyrimethamine, quinine, and mefloquine, this region has now spawned parasites resistant to Artemisinins, the world’s most potent antimalarial drugs. In areas where Artemisinin resistance is prevalent, Artemisinin combination therapies (ACTs)—the first-line treatments for malaria—are failing fast. This worrisome development threatens to make malaria practically untreatable in SEA, and threatens to compromise global endeavors to eliminate this disease. A recent series of clinical, in vitro, genomics, and transcriptomics studies in SEA have defined in vivo and in vitro phenotypes of Artemisinin resistance, identified its causal genetic determinant, explored its molecular mechanism, and assessed its clinical impact. Specifically, these studies have established that Artemisinin resistance manifests as slow parasite clearance in patients and increased survival of early-ring-stage parasites in vitro; is caused by single nucleotide polymorphisms in the parasite’s K13 gene, is associated with an upregulated “unfolded protein response” pathway that may antagonize the pro-oxidant activity of Artemisinins, and selects for partner drug resistance that rapidly leads to ACT failures. In SEA, clinical studies are urgently needed to monitor ACT efficacy where K13 mutations are prevalent, test whether new combinations of currently available drugs cure ACT failures, and advance new antimalarial compounds through preclinical pipelines and into clinical trials. Intensifying these efforts should help to forestall the spread of Artemisinin and partner drug resistance from SEA to sub-Saharan Africa, where the world’s malaria transmission, morbidity, and mortality rates are highest.

  • the threat of Artemisinin resistant malaria
    The New England Journal of Medicine, 2011
    Co-Authors: Arjen M Dondorp, Rick M Fairhurst, Laurence Slutsker, John R Macarthur, G Joel M D Breman, Philippe J Guerin, Thomas E Wellems, Pascal Ringwald, Robert D Newman, Christopher V Plowe

    Abstract:

    Since the 1970s, when Chinese researchers demonstrated the Artemisinins’ antimalarial potency, Artemisinin-based combination therapy has become key to malaria control. But reduced susceptibility of Plasmodium falciparum to Artemisinin is now being seen in some places.

  • exploring the contribution of candidate genes to Artemisinin resistance in plasmodium falciparum
    Antimicrobial Agents and Chemotherapy, 2010
    Co-Authors: Mallika Imwong, Arjen M Dondorp, Poravuth Yi, Francois Nosten, Mathirut Mungthin, Sarun Hanchana, Aung Phae Phyo, Khin Maung Lwin

    Abstract:

    The reduced in vivo sensitivity of Plasmodium falciparum has recently been confirmed in western Cambodia. Identifying molecular markers for Artemisinin resistance is essential for monitoring the spread of the resistant phenotype and identifying the mechanisms of resistance. Four candidate genes, including the P. falciparum mdr1 (pfmdr1) gene, the P. falciparum ATPase6 (pfATPase6) gene, the 6-kb mitochondrial genome, and ubp-1, encoding a deubiquitinating enzyme, of Artemisinin-resistant P. falciparum strains from western Cambodia were examined and compared to those of sensitive strains from northwestern Thailand, where the Artemisinins are still very effective. The Artemisinin-resistant phenotype did not correlate with pfmdr1 amplification or mutations (full-length sequencing), mutations in pfATPase6 (full-length sequencing) or the 6-kb mitochondrial genome (full-length sequencing), or ubp-1 mutations at positions 739 and 770. The P. falciparum CRT K76T mutation was present in all isolates from both study sites. The pfmdr1 copy numbers in western Cambodia were significantly lower in parasite samples obtained in 2007 than in those obtained in 2005, coinciding with a local change in drug policy replacing artesunate-mefloquine with dihydroArtemisinin-piperaquine. Artemisinin resistance in western Cambodia is not linked to candidate genes, as was suggested by earlier studies.

Patrick J Westfall – 2nd expert on this subject based on the ideXlab platform

  • high level semi synthetic production of the potent antimalarial Artemisinin
    Nature, 2013
    Co-Authors: Christopher J. Paddon, Patrick J Westfall, Kirsten R Benjamin, Douglas J. Pitera, Karl Fisher, Michael D. Leavell, Derek James Mcphee, A Main, Devin R Polichuk, Keat Thomas H Teoh

    Abstract:

    Saccharomyces cerevisiae is engineered to produce high concentrations of artemisinic acid, a precursor of the Artemisinin used in combination therapies for malaria treatment; an efficient and practical chemical process to convert artemisinic acid to Artemisinin is also developed. Artemisinin-based combination therapies are the treatment of choice for uncomplicated Plasmodium falciparum malaria, but the supply of plant-derived Artemisinin can sometimes be unreliable, causing shortages and high prices. This manuscript describes a viable industrial process for the production of semisynthetic Artemisinin, with the potential to help stabilize Artemisinin supply. The process uses Saccharomyces cerevisiae yeast engineered to produce high yields of artemisinic acid, a precursor of Artemisinin. The authors have also developed an efficient and scalable chemical process to convert artemisinic acid to Artemisinin. In 2010 there were more than 200 million cases of malaria, and at least 655,000 deaths1. The World Health Organization has recommended Artemisinin-based combination therapies (ACTs) for the treatment of uncomplicated malaria caused by the parasite Plasmodium falciparum. Artemisinin is a sesquiterpene endoperoxide with potent antimalarial properties, produced by the plant Artemisia annua. However, the supply of plant-derived Artemisinin is unstable, resulting in shortages and price fluctuations, complicating production planning by ACT manufacturers2. A stable source of affordable Artemisinin is required. Here we use synthetic biology to develop strains of Saccharomyces cerevisiae (baker’s yeast) for high-yielding biological production of artemisinic acid, a precursor of Artemisinin. Previous attempts to produce commercially relevant concentrations of artemisinic acid were unsuccessful, allowing production of only 1.6 grams per litre of artemisinic acid3. Here we demonstrate the complete biosynthetic pathway, including the discovery of a plant dehydrogenase and a second cytochrome that provide an efficient biosynthetic route to artemisinic acid, with fermentation titres of 25 grams per litre of artemisinic acid. Furthermore, we have developed a practical, efficient and scalable chemical process for the conversion of artemisinic acid to Artemisinin using a chemical source of singlet oxygen, thus avoiding the need for specialized photochemical equipment. The strains and processes described here form the basis of a viable industrial process for the production of semi-synthetic Artemisinin to stabilize the supply of Artemisinin for derivatization into active pharmaceutical ingredients (for example, artesunate) for incorporation into ACTs. Because all intellectual property rights have been provided free of charge, this technology has the potential to increase provision of first-line antimalarial treatments to the developing world at a reduced average annual price.

  • high level semi synthetic production of the potent antimalarial Artemisinin
    Nature, 2013
    Co-Authors: Christopher J. Paddon, Patrick J Westfall, Kirsten R Benjamin, Douglas J. Pitera, Karl Fisher, Michael D. Leavell, Derek James Mcphee, A Main, Anna Tai, Diana Eng

    Abstract:

    Saccharomyces cerevisiae is engineered to produce high concentrations of artemisinic acid, a precursor of the Artemisinin used in combination therapies for malaria treatment; an efficient and practical chemical process to convert artemisinic acid to Artemisinin is also developed.

  • Microbially derived semisynthetic Artemisinin
    Isoprenoid Synthesis in Plants and Microorganisms: New Concepts and Experimental Approaches, 2013
    Co-Authors: Christopher J. Paddon, Derek Mcphee, Patrick J Westfall, Kirsten R Benjamin, Douglas J. Pitera, Rika Regentin, Karl Fisher, Scott Fickes, Michael D. Leavell, Jack D Newman

    Abstract:

    © Springer Science+Business Media New York 2013.Artemisinin is a sesquiterpene lactone endoperoxide with potent antimalarial properties, recommended by the World Health Organization for the treatment of malaria in Artemisinin combination therapies (ACTs). It is extracted from the plant Artemisia annua, but its supplies are limited and its price is volatile. In order to increase supply and stabilize the price of Artemisinin, a semisynthesis has been developed, whereby an Artemisinin precursor (amorpha-4,11-diene) is produced in microbes and the isolated precursor converted chemically to Artemisinin. Escherichia coli has been engineered to produce amorpha-4,11-diene by the expression of a heterologous mevalonate pathway along with amorpha-4,11-diene synthase (ADS) from A. annua. Development of the E. coli platform to increase production of amorpha-4,11-diene from 24 mg/L to >25 g/L is described. ADS has also been expressed in the yeast model system Saccharomyces cerevisiae which, following manipulation of the mevalonate pathway, produced 150 mg/L of amorpha-4,11-diene. The cDNAs encoding the cytochrome P450 that oxidizes amorpha-4,11-diene to artemisinic acid, CYP71AV1, and its cognate reductase were isolated from A. annua and expressed in amorpha-4,11-diene-producing E. coli and yeast, leading to the production of >1 g/L artemisinic acid from both organisms. A route for the chemical conversion of artemisinic acid to Artemisinin is described. Production of semisynthetic Artemisinin may lead to the development of a second source of the drug for incorporation into ACTs.

Christopher J. Paddon – 3rd expert on this subject based on the ideXlab platform

  • high level semi synthetic production of the potent antimalarial Artemisinin
    Nature, 2013
    Co-Authors: Christopher J. Paddon, Patrick J Westfall, Kirsten R Benjamin, Douglas J. Pitera, Karl Fisher, Michael D. Leavell, Derek James Mcphee, A Main, Devin R Polichuk, Keat Thomas H Teoh

    Abstract:

    Saccharomyces cerevisiae is engineered to produce high concentrations of artemisinic acid, a precursor of the Artemisinin used in combination therapies for malaria treatment; an efficient and practical chemical process to convert artemisinic acid to Artemisinin is also developed. Artemisinin-based combination therapies are the treatment of choice for uncomplicated Plasmodium falciparum malaria, but the supply of plant-derived Artemisinin can sometimes be unreliable, causing shortages and high prices. This manuscript describes a viable industrial process for the production of semisynthetic Artemisinin, with the potential to help stabilize Artemisinin supply. The process uses Saccharomyces cerevisiae yeast engineered to produce high yields of artemisinic acid, a precursor of Artemisinin. The authors have also developed an efficient and scalable chemical process to convert artemisinic acid to Artemisinin. In 2010 there were more than 200 million cases of malaria, and at least 655,000 deaths1. The World Health Organization has recommended Artemisinin-based combination therapies (ACTs) for the treatment of uncomplicated malaria caused by the parasite Plasmodium falciparum. Artemisinin is a sesquiterpene endoperoxide with potent antimalarial properties, produced by the plant Artemisia annua. However, the supply of plant-derived Artemisinin is unstable, resulting in shortages and price fluctuations, complicating production planning by ACT manufacturers2. A stable source of affordable Artemisinin is required. Here we use synthetic biology to develop strains of Saccharomyces cerevisiae (baker’s yeast) for high-yielding biological production of artemisinic acid, a precursor of Artemisinin. Previous attempts to produce commercially relevant concentrations of artemisinic acid were unsuccessful, allowing production of only 1.6 grams per litre of artemisinic acid3. Here we demonstrate the complete biosynthetic pathway, including the discovery of a plant dehydrogenase and a second cytochrome that provide an efficient biosynthetic route to artemisinic acid, with fermentation titres of 25 grams per litre of artemisinic acid. Furthermore, we have developed a practical, efficient and scalable chemical process for the conversion of artemisinic acid to Artemisinin using a chemical source of singlet oxygen, thus avoiding the need for specialized photochemical equipment. The strains and processes described here form the basis of a viable industrial process for the production of semi-synthetic Artemisinin to stabilize the supply of Artemisinin for derivatization into active pharmaceutical ingredients (for example, artesunate) for incorporation into ACTs. Because all intellectual property rights have been provided free of charge, this technology has the potential to increase provision of first-line antimalarial treatments to the developing world at a reduced average annual price.

  • high level semi synthetic production of the potent antimalarial Artemisinin
    Nature, 2013
    Co-Authors: Christopher J. Paddon, Patrick J Westfall, Kirsten R Benjamin, Douglas J. Pitera, Karl Fisher, Michael D. Leavell, Derek James Mcphee, A Main, Anna Tai, Diana Eng

    Abstract:

    Saccharomyces cerevisiae is engineered to produce high concentrations of artemisinic acid, a precursor of the Artemisinin used in combination therapies for malaria treatment; an efficient and practical chemical process to convert artemisinic acid to Artemisinin is also developed.

  • Microbially derived semisynthetic Artemisinin
    Isoprenoid Synthesis in Plants and Microorganisms: New Concepts and Experimental Approaches, 2013
    Co-Authors: Christopher J. Paddon, Derek Mcphee, Patrick J Westfall, Kirsten R Benjamin, Douglas J. Pitera, Rika Regentin, Karl Fisher, Scott Fickes, Michael D. Leavell, Jack D Newman

    Abstract:

    © Springer Science+Business Media New York 2013.Artemisinin is a sesquiterpene lactone endoperoxide with potent antimalarial properties, recommended by the World Health Organization for the treatment of malaria in Artemisinin combination therapies (ACTs). It is extracted from the plant Artemisia annua, but its supplies are limited and its price is volatile. In order to increase supply and stabilize the price of Artemisinin, a semisynthesis has been developed, whereby an Artemisinin precursor (amorpha-4,11-diene) is produced in microbes and the isolated precursor converted chemically to Artemisinin. Escherichia coli has been engineered to produce amorpha-4,11-diene by the expression of a heterologous mevalonate pathway along with amorpha-4,11-diene synthase (ADS) from A. annua. Development of the E. coli platform to increase production of amorpha-4,11-diene from 24 mg/L to >25 g/L is described. ADS has also been expressed in the yeast model system Saccharomyces cerevisiae which, following manipulation of the mevalonate pathway, produced 150 mg/L of amorpha-4,11-diene. The cDNAs encoding the cytochrome P450 that oxidizes amorpha-4,11-diene to artemisinic acid, CYP71AV1, and its cognate reductase were isolated from A. annua and expressed in amorpha-4,11-diene-producing E. coli and yeast, leading to the production of >1 g/L artemisinic acid from both organisms. A route for the chemical conversion of artemisinic acid to Artemisinin is described. Production of semisynthetic Artemisinin may lead to the development of a second source of the drug for incorporation into ACTs.