Drug discovery and inventors for the treatment of malaria

Tu yo yo, female, December 30, 1930 born, pharmacy, lifelong researcher and chief researcher of Chinese Academy of TCM, director of Artemisinin Research and development center. He was hired as a master tutor in 1980 and a doctoral tutor in 2001. For many years engaged in Chinese medicine and Western medicine combined research, outstanding contribution is the creation of new antimalarial drugs ——— artemisinin and hydrogen artemisinin. In September 2011, Lasker was awarded the "Vane" award for the Nobel Prize. This is the world-class top prize that China's biomedical industry has so far won.

December 30, 1930, born in Ningbo, Zhejiang Province; 1948, entered the Ningbo effective Middle School study;
1950, entered Ningbo Middle School to study senior high;
1951, admitted to the Department of Pharmacy, Peking University Medical College;
1955, graduated from Beijing Medical College (later renamed Beijing Medical University, is now Peking University Medical Department) department of Pharmacy;
1955, distributed in the Ministry of Health (Chinese Academy of TCM) Institute of Traditional Chinese Medicine has been working today;
1959-1962, participated in the third phase of the Ministry of Health of Western medicine to learn TCM classes;
1979, deputy researcher of Chinese Academy of Traditional Chinese Medicine Research Institute;
In 1985, he was a researcher at Chinese Academy of TCM Research.

1958, was named the Ministry of Health Socialist Construction activists;
In 1978, the Artemisinin Antimalarial research project was awarded the National Science and Technology Achievement Award by the National Scientific Congress.
1979, the Artemisinin research results were awarded second Prize of National Invention Award by National Science and Technology Commission;
1984, Artemisinin was successfully developed by the Chinese Medical Association, such as "the founding of 35 since the 20 major medical science and technology achievements" one;
1987, the World Cultural Council awarded the Albert Einstein World Science Certificate;
1992, the BIS-hydrogen artemisinin by the National Science and Technology Commission as "National top ten scientific and Technological achievements Award";
1997, hydrogen artemisinin was rated as "Ten new China Health achievements" by the Ministry of Health;
2009, won the third annual (2009) Chinese Academy of TCM Down's Chinese Medicine Development Award;
In September 2011, the results of the artemisinin research were awarded to the La Basque Clinical Medicine award.
The Lasker Award is the most prestigious biomedical award in the United States and one of the world's most prestigious awards, after the Nobel Prize in Physiology or Medicine. The Yo Yo Medical Award awarded by the Butcher is the world-Class award awarded to the Chinese biomedical industry to date.
The Lasker Award has four awards: the Foundation Medicine Award, the Clinical Medicine Award, the Public Service Award and the special Contribution award. The Yo Yo was awarded the Clinical Medicine Prize for the reason that "the discovery of artemisinin, a drug used to treat malaria, has saved the lives of millions of of people globally, especially in the developing world".

Malaria is a worldwide pandemic that seriously harms human life and health. According to the World Health Organization (WHO), an estimated 1 billion people worldwide live in malaria-endemic areas, with more than 200 million people suffering from malaria each year and more than 1 million deaths from malaria. Because the Plasmodium has been resistant to quinoline drugs, malaria control has become a research topic in the world's pharmaceutical industry. Since the 60 's, the United States, Britain, France, Germany and other countries spent a great deal of manpower and material resources to find effective new structural types of compounds, but never satisfactory results. Since 1964, the new drug research on antimalarial malaria has been re-started in China, and it has been comprehensively carried out in the 7 major provinces and municipalities of the country in 1967. The search for new antimalarial drugs from Chinese herbal medicine has been the mainstream of the whole work, but there is no significant discovery through the preliminary screening of thousands of kinds of Chinese herbs.
At home and abroad are in a difficult situation, in February 1969, the slaughter Yo Yo accepted the Chinese herbal medicine anti-malarial research arduous task. She first from the collection and collation of the history of medicine, Materia Medica, local medicine records of the single, prescription, but also visited the Chinese Academy of Traditional Chinese Medicine experts, collected since the establishment of the public letters, compiled a selection from more than 2000 prescriptions of the 640 drug-based antimalarial prescriptions, and on this basis, to carry out experimental research, Tissue Rat Malaria screening. However, the screening of a large number of samples, there is no good signs. Soon, the slaughter Yo Yo obey the organization arrangement, to Hainan Island Malaria Area laboratory work for half a year long, back to Beijing, because of various reasons work difficult to carry out. In 1971, the anti-malarial team once again held a professional meeting in Guangzhou, where Premier Zhou Enlai made important instructions. Tu yo Yo also participated in this meeting, and shoulders a new task back to Beijing, the Organization force set up a task group, put into a new research.
This time, in the re-consideration of some of the better-based drug screening, she also systematic access to the relevant literature, pay special attention to the experience of medicine in the past to draw the clues to the rational extraction of drugs, in order to find a breakthrough, the Eastern Jin Ge Hong "elbow reserve urgent side," said, there is "Artemisia yi Grip, water a liter of She pondered the record and felt the great article inside. Tu yo yo According to this clue, the extraction method was improved, and the temperature was controlled by ethanol cold soaking method in 60 ℃, and the extract of Artemisia annua was significantly improved in the rat malaria potency. Then, the low-boiling solvent was used to extract the rat malaria potency and stabilize.
It was the very time of the "Cultural Revolution" when politics hit everything. In such circumstances, such as the slaughter of Yo Yo and other people are still not disturbed by the night and night to bury in the laboratory, repeated anti-malarial experimental research, and finally on October 4, 1971, that is, the 191th experiment after the Guangzhou conference (has selected more than 200 kinds of prescriptions), obtained the success of the anti-malarial Artemisia annua. The inhibitory rate of Artemisia annua was 100%, and she divided the extracts of Artemisia annua into two parts: neutral and acidic, and found that the neutral part had high anti-malarial potency and low toxicity, and the acidic part was ineffective and toxic. After confirming the neutral part as the effective part of Artemisia falciparum malaria, the experiment of monkey Malaria was carried out, and the same satisfactory effect was obtained.
Since then, she has carried out in-depth pharmacology, toxicology research, in order to ensure the safety of medication she also tried to wear. In this case, the slaughter of Yo Yo in 1972 8-October, with the relevant medical personnel carrying medicine to the Hainan Changjiang area trial, from vivax to falciparum malaria, from the local population to the field population, for the first time to obtain 30 cases of Artemisia annua anti-malaria success. In 1973, the first trial of artemisinin monomer in the same place confirmed that its antimalarial efficacy was better than that of antimalarial drug chloroquine. Then, with strong assistance from all over the country, further expansion of clinical verification, to 1978, a total of 2099 cases (including 1511 cases of vivax malaria, 588 cases of falciparum malaria), all obtained clinical recovery, so that artemisinin has truly become a new type of structural anti-malarial drugs.
On the basis of clinical evidence of effective anti-malaria of Artemisia annua, Yo yo and other people carry forward the spirit of continuous combat, and further isolate and purify the effective monomer of Artemisia annua from the part. The new compound was named "Artemisinin", which was determined as a semi-terpene component by a large number of chemical work and derivative preparations combined with four spectral studies. Due to the particularity of its structure, the chemical structure was finally determined by X-diffraction method with the support of the Institute of Biophysics of CAS and the Institute of Organic Chemistry. Artemisinin is an over-oxygen group of "semi-terpene lactone", the structure contains only carbon, hydrogen, oxygen, 3 elements, thus breaking the antimalarial drug must have a nitrogen-containing heterocyclic theory "forbidden area." The results also reveal that the anti-malarial activity of artemisinin is related to the oxygen group in the structure of "semi-terpene lactone", which lays a theoretical foundation for the reconstruction of the structure.
In March 1977, for the first time in the name of "Artemisinin structure Research Collaboration Group", the paper "a new type of semi-terpene lactone-Artemisinin" published in the "Scientific Bulletin" (1977, 3rd), has aroused close attention and attention of the world's countries.
The discovery and development of artemisinin is a major event in the history of human malaria control and a significant breakthrough after quinoline anti-malarial drugs. In October 1981, at the International Artemisinin conference hosted by the World Health Organization (WHO) in Beijing, the slaughter of Yo Yo as the chief spokesperson for the report "Chemical studies of artemisinin" has aroused great interest from representatives at home and abroad.
Professor Arnad, Chairman of the Scientific Working Group on Malaria Chemotherapy and the Director of the Central Institute for Drug Research in India, said: The new discovery, more importantly, is to discover the unique chemical structure of the compound, which will indicate the direction for further design of synthetic drugs. "In theory, any new drug has a new structure and the way it works, so that it can delay the emergence of resistance and have a longer life," the World Health Organization official said in the report. Obviously, Chinese artemisinin is in line with this requirement. The delegates agreed that artemisinin and its derivatives were invented by Chinese scientists, whose chemical structure and anti-malarial effects were completely different from the previously known antimalarial drugs, and were highly effective, quick-acting and low-toxicity for a variety of drug-resistant Plasmodium falciparum, a promising new drug.

Artemisia annua is a traditional Chinese medicine, which was first included in the 52 disease party. "Herbal Medicine Sutra", also known as Artemisia
The Yo Yo was interviewed at the 2011 Lasker Award ceremony.
The Yo Yo was interviewed at the 2011 Lasker Award ceremony.
Artemisia annua, since 340, the Eastern Jin Dynasty ge Hong "elbow reserve urgent side" after the books of various generations have the records of the treatment of malaria.
However, "original ecological Chinese Medicine" on its appearance, quality control, potency, indications, taking methods, etc., it is difficult to be accepted internationally. Therefore, the success of artemisinin-like drugs is not only a major breakthrough in the world antimalarial drugs, but also in the modernization and internationalization of traditional Chinese medicine is a model.
According to the latest who 2009 statistics, about 250 million people in the world are infected with malaria, nearly 1 million have died from Plasmodium falciparum, and if there is no artemisinin found in the slaughter of Yo yo, more than 250 million people infected with malaria will not survive. After years of research and exploration, Yo Yo, a Chinese Academy of TCM, has extracted the effective ingredient artemisinin from Chinese traditional herbal Artemisia annua, becoming the most effective malaria control drug today.
The first drug to treat malaria is quinine, a drug taken from the bark of a jinji tree. In 1934, scientists synthesized one of the medicines for malaria, chloroquine, because its toxic side effects were put on hold for at least 10 years, until two war, the United States conducted clinical trials showed that chloroquine is a very effective antimalarial drug, 1947 years before the introduction of clinical practice for the prevention and treatment of malaria. Unfortunately, some malaria parasites that have been resistant to chloroquine have emerged.
The discovery process of anti-malarial effect of Artemisia annua
Malaria, which has been a threat to human life for thousands of years, has been the cause of the disease in the 50 's, as malaria parasites have been resistant to existing antimalarial drugs such as chloroquine, and the once-suppressed epidemic has returned, and it is imperative to develop new antimalarial drugs. In 1967, with more than 60 research institutes and more than 500 plant chemistry and pharmacology researchers in China, the "523 Project", which aims to develop new antimalarial drugs as soon as possible, was formally launched in early 1969, and Yo Yo was appointed as the project leader of the "523 projects" of the Chinese Academy of TCM Research Institute. In the treasure trove of traditional medical medicine in China, we look for the effective ingredient of separating treatment of malaria.
Biologist and medical scientist, Nobel Prize laureate Joseph Golstein, said that the development of biomedicine is mainly through two different approaches, one is discovery, the other is invention, and the slaughter of Yo Yo as a plant chemist, especially during the period from the 1960s to 80, Fortunately, it was fortunate to discover artemisinin and its anti-malarial effects at the same time, creating a new milestone in the path of human antimalarial, which made a great contribution to humanity, and she and her colleagues saved millions of lives and were affirmed and highly appreciated by WHO and the world medical community.
Since 1969, the Yo Yo and her team have consulted a large number of literature, after another failure and two years of hard work, in more than 2000 kinds of Chinese herbal medicine to screen out the most promising Artemisia annua, but the initial study is not smooth, the initial experimental results are not very satisfactory.
After consulting a large number of documents, the slaughter Yo Yo in 340 A.D. in the Eastern Jin Dynasty ge Hong "elbow reserve urgent side" found in the description of the treatment of Artemisia annua (see left): "A grip of Artemisia, water two liters of stains, twisted juice, to serve." Why did the Ancients "twist the Juice" of Artemisia annua, instead of the traditional water-burning method of cooking Chinese herbs? The Yo yo realized that it was possible that boiling and high temperature extraction destroyed the active ingredient in Artemisia annua, so she changed the original extraction method, extracted its active ingredient with a low-boiling solvent of ethyl ether, and removed the acidic part, which had no anti-malarial activity and toxic side effects, and retained the anti-malarial active, safe and reliable neutral part, The effectiveness of artemisinin in the prevention and treatment of malaria has been significantly reduced as well as its toxicity. The extract of Artemisia 191, which was extracted in 1971, reached 100% in the treatment of mice infected with Plasmodium p.berghei and the monkeys infected by P.cynomolgi Plasmodium. This discovery is a significant breakthrough in the discovery process of artemisinin, an effective ingredient in Artemisia annua.
Although the transfer from China
Tu yo yo at the 2011 award Ceremony of "Lasker Prize"
Tu yo yo at the 2011 "Lasker Award" awards ceremony [10]
The medical literature has been greatly inspired, but a large number of screening and identification work needs to be done by the Yo yo in person. For example, the Artemisia annua is only a category of traditional Chinese herbal medicine, including 6 different kinds of herbs, each containing a different chemical composition, the effect of treatment of malaria is also different. Ge Hong's writings do not specify which Artemisia annua can be used to treat malaria, nor does it indicate which part of Artemisia annua is the plant, root, stalk, or leaf? "523 Project" researchers in Yunnan province found that the extract of Artemisia annua, a scientific name known as "Artemisia annua", was the most effective in treating malaria, but this effect did not recur in subsequent experiments and did not exactly match the results stated in the literature.
To find out what this is all about, the slaughter Yo yo on the one hand continue to look for the answer in the literature, on the one hand to experiment verification. After repeated experiments and analysis, the slaughter of Yo Yo found that the anti-malarial activity of Artemisia is part of the leaf, not other parts, and only fresh leaves contain artemisinin effective ingredients. In addition, the group found that the best time to harvest was before the plant was about to blossom, when the leaves contained the most abundant artemisinin. The Yo yo also analyzed and evaluated the artemisinin content of "Artemisia annua" in different localities. "All of these uncertainties are the cause of our initial research that is not ideal and unstable, and we are puzzled," she said. However, her persistence and perseverance in the study were admirable.
From molecular structure to drug development
Artemisinin treatment of malaria in animal experiments has achieved complete success, then, it is also effective for humans? Is it safe and effective to act on humans? To determine this as soon as possible, Yo Yo and her colleagues bravely acted as the first volunteers to carry out experiments on their own, in the absence of a procedure for the evaluation of drug safety and clinical efficacy, which was the only way to gain confidence in the treatment of malaria with Chinese herbal medicines. "We need to be as quick as possible to prove the clinical effect of this very hard-to-find antimalarial drug, which is the real motive for taking the drug," she says. ”
After the success of his experiments, Tu Yo yo and her team went deep into the Hainan area to conduct field trips. After a trial of 21 patients infected with Plasmodium.vivax and p.falciparum, the clinical efficacy of artemisinin in treating malaria was surprisingly good, compared with the control group of patients using chloroquine, who were treated with artemisinin quickly, and the parasite in the blood quickly disappeared.
Slaughter Yo yo The next step is to extract the effective ingredients from Artemisia annua. Before, the effective ingredient artemisinin was not purified and separated, the chemical structure of this effective ingredient is also unknown. In 1972, Yo Yo and her colleagues extracted a colorless crystalline molecule of c15h22o5 from Artemisia annua, an active ingredient with a melting point of 156℃~157℃, which they named the colorless crystalline substance artemisinin. Tu yo yo know that, as Joseph Golstein said, this discovery is only the first step, and the next step is to work creatively, and how to turn this anti-malarial natural molecule into a potent antimalarial drug.
The Yo yo of their isolated crystals, the anti-malarial effect of artemisinin, has finally found an effective anti-malarial drug. "We noticed that the patient started to have a fever, which is a sign of the elimination of symptoms and the improvement of the condition," Yo Yo said. More importantly, we also found that the parasite in the patient's blood sample disappeared. At this point, we conclude that the drug is not only a symptom-relieving, but a cure for the disease. We observed that artemisinin was able to kill it at any stage of the malaria parasite's life cycle. ”
In December 1979, artemisinin and its derivatives were tested in 2000 patients, some of which were infected with chloroquine-resistant Plasmodium falciparum, when the earliest English reports appeared.
The Yo Yo Study Group was initially tested in the form of tablets, but the results were not ideal, and later changed into a new form, the capsule of artemisinin purification, which opened the way to the invention of a new anti-malarial drug. In addition to considering the formulation and production of the drug, the Yo Yo and her team also considered how the discovery could be brought to the world for the benefit of all humankind.
In 1973, Yo yo synthesized the hydrogen artemisinin to confirm the chemical structure of the hydroxyl (group) hydroxyl family, but at the time she did not know that the chemical she had synthesized was proven to be much better than the natural artemisinin effect. In 1975, the three-dimensional chemical structure of artemisinin was determined with the assistance of Shanghai Organic Institute of CAS and the Institute of Biophysics of CAs.
Artemisinin that goes to the world
In the middle of the 70, Professor Li Guoqiao of Guangzhou University of Traditional Chinese medicine conducted clinical trials with artemisinin and its derivatives, and the results showed that artemisinin-based antimalarial drugs had better efficacy than some traditional antimalarial drugs such as chloroquine and quinine.
Following the first large-scale trial, the Keith Arrod of the Hong Kong Far East Research Foundation joined the Alain Li
Tu yo yo at the 2011 award Ceremony of "Lasker Prize"
Tu yo yo at the 2011 "Lasker Award" awards ceremony [11]
Two years after the bridge's test of Artemisinin, they published a joint article on artemisinin clinical trials. After that, they compared artemisinin with other known antimalarial drugs, and, without increasing side effects, artemisinin was significantly more effective. Years of clinical practice have shown that artemisinin is considered to be the most effective antimalarial drug available.
The chemical structure of Artemisinin was published in 1977, and in the same year, the molecular formula and related papers of artemisinin were quickly quoted by the American Chemical Digest. In 1979, the China Science and Technology Commission awarded the Yo Yo Scientific research group The work of the National Science and Technology Invention Award to recognize their discovery of artemisinin and its anti-malarial effects.
In 1981, the fourth meeting of the Anti-Malaria Research Working Group, launched by the United Nations Development Programme, the World Bank and the World Health Organization, received a warm response from artemisinin and its antimalarial efficacy. The Yo Yo, who was the first to speak at the meeting, made an academic report on the study of artemisinin. In the 80 's, artemisinin and its derivatives cured tens of thousands of people infected with the parasite in China, and aroused widespread concern around the world. In 2005, the World Health Organization announced the adoption of a strategy for artemisinin-based integrated therapy, which significantly reduced the symptoms of malaria and was widely adopted around the world, saving countless lives, mostly children in Africa.
Unfortunately, some of the malaria parasites that have become resistant to artemisinin have been present. Yo Yo, who is deeply concerned about this, said, "Like other researchers in this field, I am deeply concerned about the emergence of artemisinin-resistant Plasmodium falciparum in recent reports." Who has made the right strategic decision to do so and recommends that the single use of artemisinin treatment be discontinued in order to avoid this resistance. The widespread use of artemisinin as a malaria prevention practice in some regions is a real concern for me, a potential factor in drug resistance, and I hope that the international community will take some responsible measures to regulate malaria treatment and stop drug abuse of artemisinin. ”
When asked about the sensation of this important discovery, tu yo Yo said it was difficult to describe his mood, especially after so many failures, when he doubted that the path was right, when it was found that artemisinin is the malaria buster, the excitement of the mood is difficult to express. The Yo Yo was honored to receive the 2011 Lasker Prize, and she said she was a common plant chemistry researcher, but she was proud to be a Chinese scientist found in the Treasury of Chinese Medicine and recognized by the international scientific community.

Turn from: Everyone Chinese Medicine

Drug discovery and inventors for the treatment of malaria