Artemisinin-a gift from traditional Chinese medicine for thousands of years

Artemisinin drugs are gifts from traditional Chinese medicine! It also brought China the first Nobel Prize in medicine! Although artemisinin and its derivatives, and even compound artemether are independently developed in China, Novartis has the right to sell compound artemether overseas
.
"The successful research and development of artemisinin-based antimalarial drugs is both the pride of China's medical and academic circles, and it is also our country's regret!" Artemisinin-based drugs are gifts from traditional Chinese medicine.
In 2015, the Nobel Prize Committee officially awarded the Nobel Prize in Physiology and Medicine.
It was awarded to Tu Youyou, a Chinese scientist, in recognition of her outstanding contribution to the research of the new antimalarial drug artemisinin
.
Before understanding artemisinin, let us first understand the disease targeted by artemisinin drugs-that is, malaria
.
Malaria is an insect-borne disease caused by female Anopheles mosquitoes biting the human body and introducing the parasite Plasmodium into the human body
.
Plasmodium develops into spores in mosquitoes, and enters the blood of the human body with the bite of Anopheles mosquitoes.
It parasitizes in liver cells and red blood cells, destroys cells and proliferates in large numbers, causing the onset of clinical symptoms
.
Malaria has clinical manifestations of intermittent chills, fever, and sweating, and sometimes causes splenomegaly and anemia
.
Severe malaria patients can cause damage to the brain, liver, kidneys and other organs, and can cause damage to the circulatory system, respiratory system, and even multi-system failure
.
Malaria is divided into the following four types due to the different types of Plasmodium: Falciparum, vivax, Plasmodium ovale and Plasmodium; Plasmodium falciparum can invade red blood cells of any age, the density of Plasmodium in the blood of patients is high, and the reproduction cycle is short.
, So anemia and severe clinical manifestations; Plasmodium ovale and Plasmodium ovale often only invade naive red blood cells, and the protozoan density is low; Malaria vivax only infects senescent red blood cells, the protozoan density is the lowest, anemia and other clinical manifestations are mild
.
Malaria used to be one of the infectious diseases with the longest epidemic history, the widest impact, and the most serious harm in China.
Before the founding of New China, about 30 million people suffered from malaria each year, of which 300,000 died, and the case fatality rate was as high as 1%..
In the last century, China was one of the countries with the most severe malaria epidemic in the world
.
In the 1940s, it was estimated that more than 90% of people in China were at risk of contracting malaria; from the 1950s to the 1970s, malaria also spread widely, and its incidence reached its highest peak in 1970, at 2961.
10/100,000.
; By 2010, the incidence of malaria in China had dropped to less than 1/100,000, and the achievement of malaria-free was finally achieved.
This victory is undoubtedly encouraging
.
After understanding malaria, let us take a look at how artemisinin for malaria was discovered step by step and finally used as an antimalarial drug
.
After the 1960s, drug-resistant malaria parasites were discovered in Southeast Asia and Africa.
The traditional antimalarial drugs quinine and chloroquine are no longer effective.
The treatment of tens of millions of malaria patients is facing serious difficulties, prompting various countries.
Actively research new antimalarial drugs
.
Among them, the most effective antimalarial drug is artemisinin, a new antimalarial drug discovered in China
.
The record of malaria in Chinese medicine can be traced back thousands of years, and the use of Artemisia annua as a medicinal material is the same
.
The first mention of Artemisia annua for the treatment of malaria can be traced back to the Eastern Jin Dynasty (317-420 AD) Ge Hong’s "Elbow Reserve Emergency Recipe", and then the application of Artemisia annua and other technologies in malaria prevention and treatment is often seen in a series of historical medical works in China.
There are records, including the influential Li Shizhen’s "Compendium of Materia Medica" (Ming Dynasty, 1368-1644 AD)
.
These rich ancient records have made great contributions to the discovery and development of artemisinin
.
On May 23, 1967, the Chinese government established a national project named "523" to strengthen the research of antimalarial drugs.
In 1969, Professor Tu Youyou was selected as the research group leader of the project.
Screening new antimalarial drugs
.
In 1971, the extract of Artemisia annua attracted their special attention because it produced an ideal but unstable inhibition rate.
Tu Youyou noticed that the use of Artemisia annua L "Juice", she put forward the idea of ​​extracting active ingredients under low temperature conditions from the literature and her own understanding of Chinese medicine
.
In experiments conducted around October 1971, the substance showed a 100% surprising effect on murine malaria, which undoubtedly confirmed the effectiveness of the extract of Artemisia annua
.
Artemisinin-based antimalarial drugs composed of a compound or combination method have been determined by the World Health Organization (WHO) as the only drug method that must be used in the treatment of malaria in the world
.
The technology of using artemisinin-like drug compound plus a small dose of primequine to treat current patients to prevent the spread of malaria has also been confirmed and recommended by the WHO
.
After understanding a series of knowledge about malaria and artemisinin, everyone must be very curious about how artemisinin has an effect on malaria parasites.
Now let us enter the part of the mechanism of artemisinin
.
Artemisinin first enters the infected red blood cells, and then enters the body of the malaria parasite
.
Since the plasmodium will ingest hemoglobin in the red blood cells as a source of nutrition and energy after maturation, hemoglobin, an important component of hemoglobin, will be released, and heme can activate artemisinin, through the opening related to the oxygen bridge.
The ring reaction makes artemisinin carry deadly oxygen free radicals
.
At this time, artemisinin is like an irritated beast, killing the malaria parasite
.
Studies have shown that activated artemisinin can bind to as many as 124 substances in the body of the malaria parasite, which is involved in a variety of important physiological processes
.
The normal life activities of the plasmodium are upset by artemisinin, and they are no longer able to make waves in the red blood cells of the host. .
Someone might ask the question, whether artemisinin relies on free radicals to play a killing effect, will it cause damage to the host's own cells? The answer is no, and this is the most brilliant aspect of artemisinin.
It is like an activated switch.
Only when it reaches the red blood cells infected by the malaria parasite, it receives the danger signal from heme.
This switch will be turned on, and the whole process seems like a well-designed weapon blasting at a fixed point near the target, and people have to sigh the wonders of life
.
The resistance mechanism of artemisinin is also wonderful
.
Although artemisinin has a powerful antimalarial effect and a high-safety activation mechanism, malaria parasites have begun to evolve a cunning resistance mechanism against artemisinin
.
We know that artemisinin relies on the heme produced by the metabolism of malaria parasites for activation, but the malaria parasites actually dormant for a short period of time after invading red blood cells-the ring phase
.
During this period, the malaria parasite is like hibernation, without eating or drinking.
Without the hemoglobin leftover by the malaria parasite, artemisinin cannot wake up from a deep sleep
.
The malaria parasites seized this opportunity.
The mutation of the PfKelch13 gene in their body will prolong the dormancy period of the malaria parasite, allowing more parasites to escape the killing of artemisinin, which will lead to frequent recurrences of malaria after artemisinin treatment.

.
This is not an arms race in nature, and the subtlety of life is also vividly reflected in this process
.
The mechanism of artemisinin must be clear to everyone.
However, it is not artemisinin that is actually used in clinical practice, but its derivatives, artemether and other substances.
Then why is this, let us look at it together Just look
.
The mechanism of the action of artemisinin is explained in detail in the previous article, and the antimalarial effect of artemisinin is very strong
.
But in the specific application, some problems have been found.
From the structural formula of artemisinin, we can clearly see that the fat solubility and water solubility of artemisinin are very weak, and it is difficult to directly apply it in clinical practice
.
In fact, when many classic drugs are discovered, they cannot be directly applied to the clinic, and a certain structural modification is needed to make them into drugs and apply them. .
We can learn from the above that the effect of artemisinin is the peroxy bridge structure in its structure, and the underlying carbonyl group has nothing to do with the effect, and there is room for improvement
.
For this site, groups can be added by means of addition reactions to obtain three derivatives as shown in the figure below: artemether, artemether, and artesunate
.
Among them, the efficacy of artemether is the best among the three derivatives.
As a derivative of artemisinin, artemether has the following four advantages: First, it has good fat solubility.
This is what we are doing for artemisinin When the molecule is modified, the advantages have been anticipated.
The added methyl group increases the fat solubility of artemether and makes it possible to make better preparations.
Second, the antimalarial effect is good.
When artemisinin acts, it will happen The addition reaction produces dihydroartemisinin to play a role, and artemether has this reaction more easily.
Experiments have shown that the antimalarial effect of artemether is 10-20 times that of artemisinin; third, it is for the treatment of chloroquine, etc.
For the drug-resistant plasmodium, artemether has a better effect; fourth, artemether has fewer side effects
.
At present, the active ingredients of the most commonly used compound artemether are artemether and benzofluorenol.
The combination of the two can not only control malaria quickly but also cure malaria
.
Although artemisinin and its derivatives, and even compound artemether are independently developed in China, Novartis has the right to sell compound artemether overseas
.
"The successful research and development of artemisinin-based antimalarial drugs is both the pride of our country's medical science community, but also our country's regret!" After reading the artemisinin patent and commercialization section below, you may have a deeper understanding of this sentence
.
Artemisinin is an important drug that was originally created in China and has saved millions of malaria patients worldwide
.
Unfortunately, the commercialization of artemisinin is mainly completed by foreign pharmaceutical companies
.
In 1988, Sanofi first saw the commercial prospects of artemisinin.
They cooperated with Guilin Pharmaceutical and began to promote artemisinin alone as a drug to treat malaria in other parts of the world. .
However, the effect of treatment with artemisinin alone is not good
.
Later, in the 1990s, the Chinese Academy of Military Medical Sciences developed the compound artemether, but did not have the ability to promote the compound artemether to other countries, so I had to look for cooperation with major international pharmaceutical companies, and finally found Novartis, and combined the compound.
The overseas sales rights of artemether were sold to Novartis
.
In 2009, the US FDA approved the listing of compound artemether, which was China's first original drug approved by the FDA
.
The research and development of artemisinin is a typical example of independent innovation in China's pharmaceutical industry.
Its successful experience has provided very meaningful enlightenment to the research and development of new drugs in China.
It is mainly manifested in: 1.
Using modern science and technology to re-develop traditional Chinese medicinal materials: Traditional Chinese medicine in our country has a long history and many varieties, which is an inestimable asset
.
2.
The research and development of new drugs should be market-oriented: the market is the way to realize the value of new drugs, and whether they can achieve economic benefits is the standard for testing whether new drugs are successful
.
3.
The importance of intellectual property rights: The successful research and development of artemisinin-based antimalarial drugs is not only the pride of China's medical and academic circles, but also China's regret
.
It is not difficult to see the importance of intellectual property rights to the development of new drugs from the arduous process of artemisinin-based antimalarial drug development and the lessons of losing core patents due to incomplete intellectual property laws
.
Thanks to teacher Wu Xingxin and assistant teacher Sun Xueqing for their guidance and help, and thanks to the support of Yaodu platform
.
About the author.
They are students of Nanjing University's new drug research and development strategy course.
This article was completed by Yin Zirun, Yang Bofeng, Wang Haohan, and Yilijiaer from the two groups of Chinese new medicine students in the course
.
They are full of vigor, their fighting spirit is high, they learn new drug research and development knowledge down-to-earth, they firmly believe that I love my teacher and I love the truth more
.
They are the successors of the new generation of pharmaceutical industry, and they are the light of the future in the field of new drug research and development! *This article is only for academic content exchange, and does not constitute any medication advice! References 1.
Wang, J.
, et al.
, Haem-activated promiscuous targeting of artemisinin in Plasmodium falciparum.
Nature Communications, 2015.
6.