Team:TrinityCollegeDublin/Background

Background

Artemisinin – From exotic herb to modern drug

Artemisinin or as its Chinese name Qinghaosu, is a drug that possesses by far the most rapid action against the parasite Plasmodium falciparum- the Malaria causing parasite. The drug is also progressively being used in Plasmodium vivax malaria, in addition to being a topic of research in cancer treatment. Treatments containing an artemisinin derivative called ACTs are the standard treatment for Plasmodium falciparum Malaria nowadays.

Chemically a sesquiterpene lactone, artemisinin contains an unusual peroxide bridge, which is supposed to be responsible for its mechanism of action. Originally isolated from a plant called Artemisia annua (sweet wormwood), it can now be produced in large batches using genetically engineered microorganisms (yeast).

The medicinal value of this plant has been known to the Chinese for at least 2,000 years. But nobody really knew its properties distinctly as an antimalarial until 1967, when the Chinese army under the leadership of Mao Zedong set up project 523 to help the North Vietnamese army find a treatment for Malaria. Tu Youyou’s team isolated a useful extract of artemisinin from Artemisia annua. Tu reported that she was influenced by a traditional Chinese herbal medicine source written in 340 BC called: "The Handbook of Prescriptions for Emergency Treatments" by Ge Hong saying "A handful of qinghao immersed with two litres of water, wring out the juice and drink it all." The extracted substance, once subject to purification, proved to be a useful starting point to obtain purified artemisinin. Results were printed in the Chinese Medical Journal in 1979. The findings were met with scepticism at first, partially because the chemical structure of artemisinin, particularly the peroxide part, appeared to be too unstable to be a viable drug.



In the late 1990s, Novartis got a new Chinese patent for a combination therapy with Lumefantrine and Artemether, providing the first artemisinin-based combination treatment (ACTs). In 2006, after artemisinin had become the choice treatment for malaria, the World Health Organisation (WHO) called for an immediate cessation to single-drug artemisinin preparations in favour of combinations of artemisinin with another malaria drug, to diminish the risk of plasmodium developing resistance.

Then came the rise of semi-synthetic artemisinin. The partnership to develop it was led by PATH’s Drug Development program along with association from One World Health, with funding from the Gates Foundation. The project started in 2004, and initial project partners included the University of California, Berkeley (they donated the technology to genetically alter yeast to make artemisinic acid); and Amyris, Inc. (a biotechnology firm in California, that developed the method to enable large-scale production and established scalable processes for transfer to an industrial partner). In 2006, a team from UC Berkeley stated they had engineered Saccharomyces cerevisiae  to yield a small amount of the precursor artemisinic acid. The synthesized artemisinic acid could be purified and chemically converted into artemisinin that cost roughly $0.25 per dose. In this struggle of synthetic biology, a reformed mevalonate pathway was used, and the yeast cells were designed to express the enzyme amorphadiene synthase and a cytochrome P450 monooxygenase (CYP71AV1), both extracted from A. annua. A three-step oxidation of amorpha-4,11-diene gave the subsequent artemisinic acid. On May 8, 2013, WHO’s Prequalification of Medicines Programme announced the acceptability of semi-synthetic artemisinin for use in the assembly of active pharmaceutical ingredients. Sanofi’s API produced from semi-synthetic artemisinin (artesunate) was also qualified by WHO; it being the first semi-synthetic artemisinin derivative to be qualified. Commercial production of semi-synthetic artemisinin is now on-going at Sanofi's site in Garessio, Italy. This second source of artemisinin was poised to enable a more stable flow of key antimalarial treatments to those who needed treatment most. Production increased to roughly 50–60 tons per year in 2014, providing nearly 1/3 of the global annual need for artemisinin.

References:
1. Royal Society of Chemistry (July 2006). Artemisinin and a new generation of antimalarial drugs". Education in Chemistry.
2. Jianfang, Zhang (2006). A Detailed Chronological Record of Project 523 and the Discovery and Development of Qinghaosu (Artemisinin)
3. Douglas NM, Anstey NM, Angus BJ, Nosten F, Price RN (June 2010).  Lancet Infect Dis 10 (6): 405–16.
4. WHO calls for an immediate halt to provision of single-drug artemisinin malaria pills" WHO. 19 January 2006.
5. Pantjushenko, Elena. "Sanofi and PATH announce the launch of large-scale production of semisynthetic artemisinin against malaria". PATH.
6. Ro DK, Paradise EM, Ouellet M et al. (April 2006). "Production of the antimalarial drug precursor artemisinic acid in engineered yeast". Nature 440 (7086): 940–3.doi:10.1038/nature04640. PMID 16612385.