Everything about Artemisinin totally explained
Artemisinin is a
drug used to treat multi-drug resistant strains of
falciparum malaria. The compound (a
sesquiterpene lactone) is isolated from the shrub
Artemisia annua long used in
traditional Chinese medicine. Not all shrubs of this species contain artemisinin. Apparently it's only produced when the plant is subjected to certain conditions, most likely
biotic or
abiotic stress. It can be synthesized from
artemisinic acid.
History
Artemisia has been used by Chinese
herbalists for more than a thousand years in the treatment of many illnesses, such as skin diseases and malaria. The earliest record dates back to 200 BC, in the "Fifty two Prescriptions" unearthed from the Mawangdui Han Dynasty Tombs. Its antimalarial application was first described in Zhouhou Beji Fang ("The Handbook of Prescriptions for Emergencies"), edited in the middle of fourth century by Ge Hong. In the 1960s a research program was set up by the
Chinese army to find an adequate treatment for malaria. In 1972, in the course of this research, Tu Youyou (Chinese: 屠呦呦) discovered artemisinin in the leaves of
Artemisia annua. The drug is named
Qinghaosu in Chinese. It was one of many candidates then tested by Chinese scientists from a list of nearly 200 traditional
Chinese medicines for treating
malaria. It was the only one that was effective.
Images of the original scientific papers are available online and a book, 張劍方. 遲到的報告五二三項目與青蒿素研發紀實. 羊城晚報出版社, was published in 2006 that charts the history of the discovery.
It remained largely unknown to the rest of the world for about ten years, until results were published in a Chinese medical journal. The report was met with skepticism at first, because the Chinese had made unsubstantiated claims about having found treatments for malaria before. In addition, the chemical structure of artemisinin, particularly the
peroxide, appeared to be too unstable to be a viable drug.
For many years, access to the purified drug and the plant it was extracted from were restricted by the Chinese government. However,
Artemisia annua is a common shrub and has been found in many parts of the world, including along the
Potomac River, in
Washington, D.C.
Currently, artemisinin is widely used in China and Southeast Asia for treatment of malaria. It is often used without taking precautions against conditions that might lead to resistance of the malaria parasite to this drug, leading to concern that the effectiveness of artemisinin may be reduced in the near future, as is the case with other classes of
antimalarial drugs.
Because artemisinin itself has physical properties such as poor
bioavailability that limit its effectiveness, semi-synthetic
derivatives of artemisinin, including
artemether and
artesunate, have been developed. However, their activity isn't long lasting, with significant decreases in effectiveness after one to two hours. To counter this drawback, artemisinin is given alongside
lumefantrine to treat uncomplicated falciparum malaria. Lumefantrine has a half-life of about 3 to 6 days. Such a treatment is called ACT (artemisinin-based
combination therapy); other examples are artemether-lumefantrine, artesunate-
mefloquine, artesunate-
amodiaquine, and artesunate-
sulfadoxine/
pyrimethamine. Recent trials have shown that ACT is more than 90% effective, with a recovery of malaria after three days, especially for the
chloroquine-resistant
Plasmodium falciparum.
The
World Health Organisation has recommended that a switch to ACT should be made in all countries where the malaria parasite has developed resistance to
chloroquine. Artemisinin and its derivatives are now standard components of malaria treatment in China, Vietnam, and some other countries in Asia and Africa, where they've proved to be safe and effective anti-malarial drugs. They have minimal adverse side effects. Currently, artemisinin isn't widely available in the United States or Canada, but is easy to find in Africa and Asia. There have been some concerns about the quality of some products on offer in Africa.
To counter the present shortage in leaves of
Artemisia annua, researchers have been searching for a way to develop artemisinin artificially in the laboratory. A recent paper in
Nature presented a genetically engineered yeast that can synthesize a precursor called artemisinic acid which can be chemically converted to Artemisinin. The compound called
OZ-277 (also known as
RBx11160), developed by Jonathan Vennerstrom at the
University of Nebraska, has proved to be even more effective than the natural product in test-tube trials. A six month trial of the drug on human subjects in Thailand was started in January 2005. There are also plans to have the plant grow in other areas of the world outside Vietnam and China (Kenya,Tanzania,Madagascar).
Analogues
There are a number of derivatives and
analogues within the artemisinin family:
Cancer treatment
Artemisinin is under early research and testing for
treatment of
cancer, primarily by researchers at the University of Washington. Artemisinin has a
peroxide lactone group in its structure. It is thought that when the peroxide comes into contact with high iron concentrations (common in cancerous cells), the molecule becomes unstable and releases
reactive oxygen species. It has been shown to reduce
angiogenesis and the expression of
vascular endothelial growth factor in some tissue cultures.
Mechanism of action
The specific
mechanism of action of artemisinin isn't well understood, and there's ongoing research directed at elucidating it. When the parasite that causes malaria infects a red blood cell, it consumes hemoglobin and liberates free
heme, an iron-porphyrin complex. The iron reduces the peroxide bond in artemisinin generating high-valent iron-oxo species, resulting in a cascade of reactions that produce reactive oxygen
radicals which damage the parasite leading to its death.
Numerous studies have investigated the type of damage that these oxygen radicals may induce. For example, Pandey
et al. have observed inhibition of digestive vacuole cysteine protease activity of malarial parasite by artemisinin. These observations were further confirmed by ex vivo experiments showing accumulation of hemoglobin in the parasites treated with artemisinin, suggesting inhibition of hemoglobin degradation. They found artemisinin to be a potent inhibitor of hemozoin formation activity of malaria parasite.
A 2005 study investigating the mode of action of artemisinin using a yeast model demonstrated that the drug acts on the electron transport chain, generates local reactive oxygen species, and causes the depolarization of the mitochondrial membrane.
Artemisinins have also been shown to
inhibit PfATP6, a
SERCA-type
enzyme (calcium transporter) and artemisinin has been shown to compete with
thapsigargin for SERCA binding, though artemesinin is much less toxic to mammalian cells. These experiments however, have only been conducted in a recombinant system (
Xenopus oocytes), and it remains to be verified within
P. falciparum parasites. Resistance to artemisinin is conferred by a single mutation in the calcium transporter (PfATP6). This mutation has been studied in the laboratory but recently a study from French Guiana in field isolates of malaria parasites has identified a different mutation in the calcium transporter (PfATP6) that's associated with resistance to artemether, lending support to the idea that PfATP6 is the target for artemisinins.
Dosing
The WHO approved adult dose of co-artemether (artemether-lumofantrine) for malaria is
4 tablets at 0, 8, 24, 36, 48 and 60 hours (six doses). This has been proven to be superior to regimens based on
amodiaquine. Artemesinin isn't soluble in water and therefore
Artemesia annua tea was postulated not to contain pharmacologically significant amounts of artemesinin.. However, this conclusion was rebuked by several experts who stated that hot water (85
oC), and not boiling water, should be used to prepare the tea. Although Artemisia tea isn't recommended as a substitute for the ACT (artemisinin combination therapies) more clinical studies on artemisia tea preparation are needed.
The artemesinins are not used for malaria prophylaxis (prevention) because to be efficacious, they must be taken twice or three times a day throughout the risk period.
Synthesis
In 2006 a team from Berkeley published an article claiming that they'd engineered
Saccharomyces cerevisiae microbes that can produce the precursor artemisinic acid. The synthesized artemisinic acid can then be transported out, purified and turned into a drug that they claim will cost roughly 0.25 cents per dose. Details of the formation of artemisinic acid involves a mevalonate pathway, expression of amorphadiene synthase, a novel cytochrome P450 monooxygenase (CYP71AV1) and its redox partner from A. annua. A three-step oxidation of amorpha-4,11-diene gives the resulting artemisinic acid.
Amyris Biotechnologies
is collaborating with
UC Berkeley and the
Institute for One World Health to further develop this technology.
Using seed supplied by Action for Natural Medicine (ANAMED), the World Agroforestry Centre (ICRAF) has developed a hybrid, dubbed A3, which can grow to a height of 3 m and which produces 20 times more artemisinin than wild varieties. In northwestern Mozambique, ICRAF is working together with a medical organisation, Médecins sans frontières (MSF), ANAMED and the Ministry of Agriculture and Rural Development to train farmers on how to grow the shrub from cuttings, and to harvest and dry the leaves to make artemisia tea. Cultivation of this crop may well prove a valuable niche market for Africa, given the strong demand for the plant from pharmaceutical laboratories.
The biosynthesis of artemisinin is shown at the bottom in three parts: The formation of IPP and DMAPP, the formation of E,Z-FPP and finally the formation of Artemisinin.
The total synthesis of Artemisinin can also be performed using basic organic reagents. In 1982, G. Schmid and W. Hofheinz published a paper showing the complete synthesis of artemisinin. Their starting material was (-)-Isopulegol (2) which as converted to
methoxymethyl ether (3). The ether was hydroborated and then underwent oxidative workup to give (4). The primary hydroxyl group was then benzylated and the methoxymethyl ether was cleaved resulting in (5) which would be oxidized to (6). Next, the compound was protonated and treated with (E)-(3-iodo-1-methyl-1-propenyl)-trimethylsilane to give (7). This resulting ketone was reacted with lithium methoxy(trimethylsily)methylide to obtain two diastereomeric alcohols, (8a) and (8b). 8a was then debenzylated using (Li, NH3) to give lactone (9). The vinylsilane was then oxidized to ketone (10). The ketone was then reacted with fluoride ion that caused it to undergo desilylation, enol ether formation and carboxylic acid formation to give (11). An introduction of a hydroperoxide function at C(3) of 11 gives rise to (12). Finally, this underwent photooxygenation and then treated with acid to produce artemisinin.
Further Information
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