Discovery of artemisinin from Chinese herbal garden

Business News Agency September 14 artemisinin, an antimalarial drug Since Tu youyou and her colleagues discovered artemisinin from Artemisia annua L, a Chinese herbal plant, many artemisinin derivatives have been synthesized, including dihydroartemisinin, which has better activity than artemisinin In order to protect this important antimalarial drug, artemisinin combined with another drug is the only widely used treatment According to the fact that artemisinin's antimalarial activity depends on its oxygen bridge, we may be able to synthesize more new antimalarial drugs in the future This year's Lasker DeBakey clinical medical research award was awarded to Tu Youyou, a Chinese scientist, for her outstanding contribution to the discovery of artemisinin and its application in the treatment of malaria This major discovery in the history of medical development saves millions of malaria patients' lives every year all over the world, especially in developing countries In the field of basic biomedicine, the value and benefit of many important discoveries are not obvious in the short term But there are also a few whose birth has an immediate effect on the improvement of human health One such example is artemisinin, an antimalarial drug developed by Tu youyou and her colleagues Since the end of 1990s, artemisinin as a first-line drug for malaria has saved countless lives, most of which are children living in the poorest areas of the world The hope brought by the 523 project may be inconceivable that the story of artemisinin originally began in the period of the Chinese Cultural Revolution and the war of aiding Vietnam and the United States In the Vietnam War, because of the prevalence of malaria, soldiers of both sides were infected with malaria, which seriously affected the combat effectiveness of the troops The emergence of chloroquine resistant Plasmodium falciparum became the main problem of malaria control at that time, which also prompted the governments of both sides to invest a lot in the research and development of new antimalarial drugs The U.S effort led to the discovery of mefloquine Data show that patients infected with chloroquine resistant Plasmodium can be cured with a single dose of mefloquine (trenholme et al., 1975) However, due to the lack of corresponding research institutions and research conditions of the then North Vietnamese government, they had to turn to China instead On May 23, 1967, under the instruction of Chairman Mao Zedong and Premier Zhou Enlai, researchers from all over the country gathered in Beijing to hold a collaborative meeting on the research of malaria control drugs and drug resistance; a project with the nature of national secret and code name of "523 project" was launched More than 500 researchers from more than 60 research institutions and units participated in the project (Zhang Jianfang et al 2006) The short-term goal of the project is to develop drugs that can effectively control malaria on the battlefield as soon as possible (three control programs have been established by 1969), and its long-term goal is to develop new antimalarial drugs by screening synthetic compounds, Chinese herbal medicines and folk therapies Due to the nature of "523 project" as a military secret, the research results of the project are not allowed to be published During the cultural revolution, it was impossible to publish scientific papers This kind of reason led to the work was not known by people outside the 523 project at that time, but the research information and progress of the subject were freely exchanged in the form of reports in the internal meeting of researchers Without literature and published records, who is the main contributor of artemisinin discovery? When we (Miller and Sue) started exploring the history of artemisinin research and development in 2007, we didn't know the answer to the question After in-depth investigation and research, we have no doubt come to the conclusion that Professor Tu youyou of Beijing Institute of traditional Chinese medicine of Chinese Academy of Sciences is the first contributor to discover artemisinin In January 1969, Tu youyou was appointed as the leader of 523 research group of Beijing Institute of traditional Chinese medicine, leading the search and sorting of traditional Chinese medicine literature and formula In October 1981, Tu Youyou, on behalf of the 523 project in Beijing, reported the results of artemisinin treatment for malaria to the World Health Organization researchers who visited for the first time (TU, 1981) In the process of investigation and collection from ancient prescriptions to modern medicines, Tu youyou and her team members screened more than 2000 Chinese herbal prescriptions and sorted out 640 kinds of antimalarial prescriptions They tested more than 200 Chinese herbal prescriptions and more than 380 Chinese herbal extracts using Plasmodium mouse as a model In the study, they found that Artemisia annua L., a species of AI in Compositae, had a 68% inhibition rate on Plasmodium However, the subsequent experimental results showed that the inhibition rate of Artemisia annua extract to Plasmodium was only 12-40% According to Tu, the low inhibition rate may be due to the low concentration of active ingredients in the extract So they started to improve the extraction method Through reading the ancient literature, especially in the book "elbow reserve emergency prescription" written by Ge Hong (283-343 AD), a famous doctor in the Eastern Jin Dynasty, she realized that the common methods of boiling and high-temperature extraction may destroy the effective components of Artemisia annua As expected, the researchers got a better antimalarial effect of Artemisia annua extract after using ether to extract at low temperature However, the Artemisia extract obtained in this way still has toxicity and side effects In view of this situation, Professor Tu further removed the acidic part of Artemisia annua extract which had no antimalarial effect but kept the neutral part which had low toxicity and improved antimalarial ability In a rat malaria test conducted in October 1971, they found that the neutral Artemisia extract (No 191) had a 100% inhibition rate on Plasmodium At the 523 conference held in Nanjing on March 8, 1972, Tu youyou reported the result Some key refining parameters provided by Professor Tu at the meeting also accelerated the process of purification of Artemisia annua crystal In the next few months, although Tu youyou's research team encountered some setbacks in obtaining high-quality Artemisia annua crystals, the other two teams (Luo Zeyuan of Yunnan Pharmaceutical Research Institute and Wei Zhenxing of Shandong Institute of traditional Chinese medicine, etc.) soon started to use the information and extraction methods provided by Tu youyou from the local Artemisia annua L L is called Artemisia annua or Artemisia annua, and there is still controversy) The pure Artemisia annua crystal with good anti Plasmodium effect has been extracted In the clinical experiment hosted by Li Guoqiao group of Guangzhou University of traditional Chinese medicine, artemisinin extracted by Yunnan Institute of Medicine showed excellent antimalarial effect Interestingly, the X-ray diffraction crystal structure and pharmacology of artemisinin, as well as the academic papers of artemisinin against non severe malaria and severe cerebral malaria only have the signature of artemisinin research collaboration group and no individual name (1979) In this paper, artemisinin is a sesquiterpene lactone with peroxy group The peroxy group in the structure is related to the antimalarial activity of artemisinin (Fig 1) In 1985, Klayman of Walter Reed Army Institute of research (WRAIR) isolated a compound similar to artemisinin from Artemisia annua growing on the Bank of Potomac River Klayman found that only a few natural ingredients in plants contain peroxygens Although WRAIR researchers tested a large number of hydroxyl peroxides, no antimalarial activity was found (Klayman, 1985) Two clinical studies, led by Professor Li Guoqiao of Guangzhou University of traditional Chinese medicine, compared artemisinin with mefloquine In this study, they proposed for the first time that in order to prevent the recurrence of malaria and the emergence of drug-resistant Plasmodium, compound drug therapy should be considered (Jiang et al., 1982; Li et al., 1984) Compared with mefloquine, artemisinin has the characteristics of high efficiency and quick effect, which can remove parasites in a few hours However, the half-life of artemisinin is short In order to obtain better therapeutic effect, artemisinin should be used in combination with another drug Patients treated with artemisinin can recover quickly, but if they stop taking artemisinin too early, it will lead to the recurrence of malaria symptoms This incomplete cure may lead to the emergence of drug-resistant Plasmodium Li Guoqiao's research team has also developed an artemisinin containing suppository for the treatment of cerebral malaria, which has been used clinically in Africa The use of suppository shortens the treatment period and improves the survival rate After learning that the Chinese discovered artemisinin, Nick white, a professor at Oxford University in Thailand, began to study artemisinin and its derivatives He confirmed that artemisinin and its derivatives have the characteristics of antimalarial efficacy, and spared no effort to advocate the combination of artemisinin and its derivatives with another partner drug to completely eliminate Plasmodium At present, artemisinin compound has become the standard treatment for malaria in the world Thanks to his important contributions in these areas, Nick White won the Canada Gairdner award in 2010 In addition to the discovery of artemisinin, the 523 project also developed a variety of drugs that can be combined with artemisinin, including lumefantrine, piperaquine and pyronaridine The success of "523 project" reflects its unique and cooperative spirit, which integrates the advantages of many research units and researchers An important but unanswerable question in the ongoing fight against drug resistance is how long will the efficacy of artemisinin or its derivatives last in the future? Maybe we can learn something from the history of other antimalarial drugs Before the introduction of quinine, a natural drug, malaria was a disease with high mortality worldwide The use of quinine rapidly reduced malaria mortality in humans In Italy, the decrease of quinine price leads to the increase of quinine usage, which leads to the sharp decrease of patient mortality When Plasmodium falciparum is resistant to the synthetic antimalarial drug chloroquine, it is not surprising that the malaria mortality rate of children increases rapidly After chloroquine resistance was identified to be caused by mutations in the coding gene of pfcrt transporter located in Plasmodium (fidock et al., 2000), it was also clarified that these mutations were not from Africa, but from Southeast Asia to Africa (Wooton et al., 2002) One of the major challenges facing public health organizations in African countries and regions is to decide when to change malaria treatment strategies Because of the limited choice of treatment, a careful evaluation of its efficacy is needed before a decision is made to change the treatment However, in the process of changing therapy, the death of patients (especially children) often occurs before the introduction of new therapy Sulfadoxine pyrimethamine (trade name: Fansidar) is an antimalarial combination drug introduced into Africa after chloroquine Shortly after its use, a large number of reports indicated that Plasmodium falciparum had developed resistance to versida It has been shown that the occurrence of versida resistance is caused by mutations in the genes encoding dihydrofolate reductase and dihydropterate synthetase of Plasmodium Similarly, the introduction of mefloquine as a single antimalarial drug into Asia also resulted in drug resistance Unfortunate