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https://en.wikipedia.org/wiki/Artemisinin

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Artemisinin (/& n/) and its semisynthetic derivatives are a group of drugs used against malaria due to Plasmodium falciparum.[1] It was discovered in 1972 by Tu Youyou, who was co-recipient of the 2015 Nobel Prize in Medicine for her discovery.[2] Treatments containing an artemisinin derivative (artemisinin-combination therapies, ACTs) are now standard treatment worldwide for P. falciparum malaria[citation needed].

Artemisinin is isolated from the plant Artemisia annua, sweet wormwood, a herb employed in Chinese traditional medicine. A precursor compound can be produced using a genetically-engineered yeast, which is much more efficient than using the plant.[3]

Chemically, artemisinin is a sesquiterpene lactone containing an unusual peroxide bridge. This endoperoxide 1,2,4-trioxane ring is responsible for the drug’s mechanism of action. Few other natural compounds with such a peroxide bridge are known.[4]

Artemisinin and its derivatives have been used for the treatment of malarial and parasitic worm (helminth) infections. They have the advantage over other drugs in having an ability to kill faster and kill all the life cycle stages of the parasites.[5] But low bioavailability, poor pharmacokinetic properties and high cost of the drugs are major drawbacks of their use.[6] Use of the drug by itself as a monotherapy is explicitly discouraged by the World Health Organization,[7] as there have been signs that malarial parasites are developing resistance to the drug. Therapies that combine artemisinin or its derivatives with some other antimalarial drug are the preferred treatment for malaria.[8]

The partnership to develop semisynthetic artemisinin was led by PATH’s Drug Development program (through an affiliation with OneWorld Health), with funding from the Bill & Melinda Gates Foundation. The project began in 2004, and initial project partners included the University of California, Berkeley (which provided the technology on which the project was based – a process that genetically altered yeast to produce artemisinic acid)[61] and Amyris (a biotechnology firm in California, which refined the process to enable large-scale production and developed scalable processes for transfer to an industrial partner).

In 2006, a team from UC Berkeley reported they had engineered Saccharomyces cerevisiae yeast to produce small amount of the precursor artemisinic acid. The synthesized artemisinic acid can then be transported out, purified and chemically converted into artemisinin that they claim will cost roughly US$0.25 per dose. In this effort of synthetic biology, a modified mevalonate pathway was used, and the yeast cells were engineered to express the enzyme amorphadiene synthase and a cytochrome P450 monooxygenase (CYP71AV1), both from A. annua. A three-step oxidation of amorpha-4,11-diene gives the resulting artemisinic acid.[62]

The Berkeley method was augmented using technology from various other organizations. The final successful technology is based on inventions licensed from UC Berkeley and the National Research Council (NRC) Plant Biotechnology Institute of Canada.

Commercial production of semisynthetic artemisinin is now underway at Sanofi’s site in Garessio, Italy. This second source of artemisinin is poised to enable a more stable flow of key antimalarial treatments to those who need them most.[63] The production goal is set at 35 tonnes for 2013. It is expected to increase to 50–60 tons per year in 2014, supplying approximately one third of the global annual need for artemisinin.

On May 8, 2013, WHO’s Prequalification of Medicines Programme announced the acceptability of semisynthetic artemisinin for use in the manufacture of active pharmaceutical ingredients submitted to WHO for prequalification, or that have already been qualified by WHO.[64] Sanofi’s active pharmaceutical ingredient (API) produced from semisynthetic artemisinin (artesunate) was also prequalified by WHO on May 8, 2013, making it the first semisynthetic artemisinin derivative prequalified.

In 2010, a team from Wageningen University reported they had engineered a close relative of tobacco, Nicotiana benthamiana, that can also produce the precursor artemisinic acid.[65]