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Recently, a study led by Cambridge University found that ursodeoxycholic acid, a commonly used liver drug, can affect COVID-19. It can reduce the number of ACE-2 receptors on cells and make it more difficult for viruses to enter human cells.
In the experiment, the researchers confirmed that ursodeoxycholic acid is a drug that can be used to prevent COVID-19's disease by cultivating organs, donating organs, animals and humans.
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(Source: Nature)
Among them, all six untreated hamsters were infected with COVID-19 virus, and they began to lose weight after getting sick. Of the 9 animals pretreated with ursodeoxycholic acid, only 3 were infected, and the severity of the disease was low.
Subsequently, they infected two donated human lungs with COVID-19. The results showed that the lung pretreated with ursodeoxycholic acid had obvious anti-infection effect.
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Figure | Lung Perfusion (Source: Teresa Brevini)
In the follow-up experiment, 8 human volunteers received normal dose of ursodeoxycholic acid. After that, they received nasal swab test, and the results showed that the concentration of ACE2 receptor on nasal epithelial cells decreased significantly.
This means finding a way to close the door of the virus, which can prevent it from entering human cells from the beginning, thus protecting us from infection.
Because the treatment of this drug is aimed at human cells, not viruses. Therefore, it is expected to have a similar preventive effect on new variants of future viruses and other possible coronaviruses.
On February 5th, 65438, a related paper was published in Nature, entitled "FXR inhibition may protect against novel coronavirus infection by reducing ACE2".
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Figure | Related papers (Source: Nature)
For example, if the virus is an "enemy", whenever we meet different "enemies", we should make a "tailor-made" "weapon", that is, a vaccine. The use of ursodeoxycholic acid is from our point of view, by increasing our own "strength" and destroying many "enemies" with the same "trick".
Xu Jian He, a professor of biochemistry at East China University of Science and Technology, said that ursodeoxycholic acid (UDCA) is a naturally secreted chiral molecule with physiological activity in human body and belongs to steroid compounds.
Although it is rarely secreted in human body, it can enhance the activity and metabolic function of liver cells, and there is no report of toxic and side effects on human body.
At the same time, ursodeoxycholic acid has also been approved for clinical application, and it has been found that it has the functions of benefiting gallbladder, treating cholesterol stones, cholestatic liver disease and preventing the formation of drug-induced stones.
According to another report, this research led by Cambridge University shows that COVID-19 can invade human cells without a receptor called ACE2, and ursodeoxycholic acid can "lock the door".
If it can be confirmed in larger clinical trials, ursodeoxycholic acid may become an important drug to protect those high-risk groups who have not been vaccinated or whose vaccine efficacy has failed.
As we all know, vaccines protect us by strengthening the human immune system, that is, they can identify and eliminate viruses, or at least weaken them. However, the vaccine is not completely effective for patients with weak immune system.
Besides, not everyone can be vaccinated. In addition, the virus can mutate into new variants, thus producing antibodies in the body, and then the vaccine effect will be reduced.
Ursodeoxycholic acid can protect us from COVID-19 infection, and this method does not depend on the immune system, so it can supplement vaccination.
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Close the "door" of COVID-19 infection.
In the cooperative team led by Cambridge University, one member has studied organ-like diseases and used "mini bile duct" to study bile duct diseases. Another member used to mainly study the liver and cultivate miniature liver, so-called organ-like, to study the development, treatment and prevention of liver disease.
When novel coronavirus appeared in COVID-19 in 2020, the research team also turned its attention to this new threat. Later, they found that the surface of liver cells carried a large number of ACE-2 molecules. This surprised them, because it is the receptor of novel coronavirus. Previously, the research team did not know that the liver would be particularly infected or affected by COVID-19 virus.
Using a similar method, the research team accidentally discovered a molecule called FXR(farnesoid X recepto), which exists in a large number of these bile duct organs.
They also found that by directly regulating the virus, it can enter the "gate" used by cells, that is, the ACE2 receptor, thus effectively reducing its existence, just like "closing the door".
Subsequently, they studied how the number of ACE2 receptors on hepatocytes was controlled. The results showed that there was an interesting mechanism: there was a high concentration of ACE2 receptor in bile duct and gallbladder epithelial cells.
However, if it is not washed with bile acid regularly, the expression of ACE2 will be lost. When the medium contains no bile acid, the cell loses its ACE2 receptor. Therefore, they determined that bile acids can be used as modulators of ACE2 receptors.
The mechanism behind this is more complicated: bile acids can activate FXR receptors, thus stimulating the production of ACE2. If there is no bile acid, the FXR receptor cannot be activated, and there is no ACE2 receptor.
Similarly, inhibition of bile acids can also reduce the number of ACE2 receptors in lung and intestine. Of course, they also want to know whether this correlation also exists in COVID-19's target tissues, that is, lungs and intestines.
In the paper, the researchers said that they also found FXR receptors in organs produced by lung or intestinal cells, which indicated that bile acids could lead to the increase of FXR receptors, which in turn led to the increase of ACE2 receptors.
The next question is whether this process can also be reversed: that is, can the number of ACE2 receptors be reduced in this way?
Fortunately, there are drugs on the market that can reduce the concentration of bile acids in liver diseases. The research team added these substances to different organs of the liver, lungs and intestines. The results showed that the concentration of ACE22 receptor did decrease.
Along this line of thought, they experimented with ursodeoxycholic acid and found that it can act on FXR and reduce ACE2 receptors in human cells.
In addition, the same method can also close the ACE2 "gate" of organ-like "mini-lung" and "mini-intestine". As mentioned above, lung and intestine are the two main targets of COVID-19, so closing this "gate" can prevent virus infection.
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Figure | Lung Organs (Source: Teresa brevini)
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It has been successful in both mouse experiments and human experiments.
The next step is to prove that this drug can not only prevent infection of cells cultured in the laboratory, but also prevent infection of organisms.
Experiments have proved that this drug can prevent hamsters from being infected with the virus. In the past, this experiment was also regarded as the "gold standard" model for preclinical testing of anti-COVID-19 drugs.
More importantly, hamsters treated with ursodeoxycholic acid can resist the Delta strain (the latest COVID-19 strain in the experiment). At that time, the effectiveness of mainstream vaccines against the virus had been proved to have declined.
Next, the research team infected COVID-19 with liver, lung and intestinal-like organs, which they obtained from infected patients' nasal swabs. For some of these organs, ursodeoxycholic acid is used for pretreatment; And others don't.
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Figure | Bile duct/liver organ treated with ursodeoxycholic acid and exposed to novel coronavirus, red indicates virus (image source: Teresa Brevini).
The results show that this drug will make the infection rate drop sharply. ACE2 receptors in nasal, lung, liver and intestinal epithelial cells of mice and hamsters taking the drug also decreased significantly.
In other words, this drug can protect hamsters from virus infection, which proves that it can effectively prevent infection.
Of course, the research team wants to show this in humans, not hamsters. Later, they studied donated human lungs. Both lungs were perfused with drugs so that the effects of drugs on the same organ could be examined. They perfused one lung with a standard concentration of therapeutic drugs and the other with a placebo.
At the beginning of the experiment, the level of ACE2 in both lungs was the same, and then it changed, and the number of ACE2 receptors in lungs perfused with drugs decreased sharply.
The serum concentration of ACE2 in patients with congenital liver disease who have taken drugs for a long time is also lower than that in patients who have not taken drugs.
Finally, after analyzing the data of patients with COVID-19's disease and liver disease at the same time, they also found that the course of disease of patients treated with this drug was obviously lighter, relatively few patients needed intensive care, and the mortality rate was relatively low.
This discovery may also be important for organ transplantation. Considering the risk of transmission through transplanted organs in COVID-19, it may be helpful for drug treatment before organ transplantation.
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A COVID-19 drug with low cost and low side effects is expected to be born.
The researchers pointed out that although appropriate randomized controlled trials are needed to confirm these findings. However, the evidence provided by the experimental data is convincing, that is, ursodeoxycholic acid can be used as a drug to prevent COVID-19 and assist vaccination, especially among vulnerable groups.
Because it directly targets ACE2 receptor, they hope it can influence the evolution of COVID-19 synapse to cope with possible virus mutation.
It can be said that the biggest challenge in formulating intervention measures in COVID-19 is the constant emergence of new virus mutations. This discovery has brought real progress to the low-cost, safe and universal treatment, and also provided a new potential method for human beings to fight the current and future COVID-19 infection.
In the research, the research team used all conceivable methods to prove that ursodeoxycholic acid can really keep the virus out, thus protecting us from COVID-19 virus infection. More importantly, this drug acts on our cells, so it is not affected by virus mutation, even if new mutant strains appear, it may be effective.
At the same time, it is an "affordable and effective" way. Ursodeoxycholic acid has been used in clinic for many years, and it has been proved that it is not only safe, but also well tolerated, so it can be directly used in high-risk groups in COVID-19. Unlike viruses, the human body's own ACE2 receptor will not change, so the risk of drug resistance is small.
At the same time, the medicine is low in price, can be produced in large quantities, is easy to store or transport, and can be deployed quickly and conveniently. Researchers are even optimistic that this drug may become an important weapon to fight the COVID-19 epidemic.
Of course, appropriate clinical trials are needed to verify this hope. But if it is successful, a drug with low cost and little side effects will be born, which can be quickly promoted around the world.
According to Xu Jianhe's analysis, it may take a long time for ursodeoxycholic acid to be listed as a related drug in COVID-19. Although there are related ursodeoxycholic acid tablets, its indications are not diseases caused by COVID-19, so it still needs to be used as a drug in COVID-19 from clinical trials.
"However, compared with the clinical trials of brand-new drugs, it may speed up the phase I clinical trials of drug safety and reliability. At present, more clinical trials are needed to reveal whether it has the actual effect of preventing and treating COVID-19's infection symptoms, "Xu Jian said.
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Xu Jianhe: Start the artificial synthesis of ursodeoxycholic acid and find another way to save the black bear.
In fact, Xu Jianhe's team began to study the enzymatic synthesis of ursodeoxycholic acid from about 20 12.
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Figure | Xu Jianhe (Source: Xu Jianhe)
He said: "By chance, I saw a news report that the source of ursodeoxycholic acid still depends on the live bear bile extraction technology criticized by the international community, so I immediately decided to start the research on synthetic methods. The original intention at that time was to find another way to save the black bear. "
"Because our team's main research direction is to use modern biotechnology such as enzyme engineering to synthesize functional molecules with a single chiral isomer; It is also the mission and charm of synthetic biology to change the production mode of ursodeoxycholic acid from animal extraction to green and efficient biosynthesis. " Xu Jianhe added.
At present, Xu Jianhe and his team are using synthetic biology and a new generation of multi-enzyme cascade catalysis technology to synthesize key functional molecules that are useful in clinic or industry but difficult to obtain on a large scale.
"One of the important application directions is chiral pharmaceutical raw materials and their key intermediates, and ursodeoxycholic acid is one of our representative products." Xu Jianhe finally said.
Support: Ren, Bao
References:
1.Brevini, T., Maes, M., Webb, G.J. and other FXR inhibitors may protect against novel coronavirus infection by reducing ACE2. Nature (2022). https://doi . org/ 10. 1038/s 4 1586-022-05594-0
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Comment 46
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User uviqb0u
18
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Hurry up research and production, control virus infection and let people live a healthy and happy life.
Tencent users 19 days ago
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Ahuadou
20
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This medicine has existed for decades. It is called ursodeoxycholic acid tablets.
Tencent users 19 days ago
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User j 1bur8c
15
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It is hoped that Professor Xu's synthetic ursodeoxycholic acid will be listed in batches as soon as possible. Now you need it in times of panic, and bears can avoid pain!
Tencent users 19 days ago
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User i084dpk
nine
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It's been years. Let's buy a box for more than 200 days.
Tencent users 19 days ago
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User cvje9i5
four
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Bear gall? Have you seen the video of Subile? It's too painful.
Tencent users 19 days ago
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User 7b7s7t0
four
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This is a drug name that has nothing to do with bears, right? This is a medicine for treating hepatitis. Ten years ago, it was 300 boxes and 30 tablets.
Tencent users 19 days ago
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Paul
six
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It seems that I am invincible, ahead of COVID-19!
Tencent users 19 days ago
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Yiyukou China
1
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I have taken this medicine for more than half a year. Can be used for preventing recurrence of bile duct stones. One pill a day, imported from Germany, not cheap. Domestic products are relatively cheaper, but they are also quite expensive.
Tencent users 19 days ago
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User 424 1772
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Then you must not be infected.
Tencent users 18 days ago
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Henry (smirking)
five
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Is that bear bile Fritillaria seller crazy again?
Tencent users 19 days ago
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Xiaoweizi
10
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It's called Fritillaria serpentina.
Tencent users 19 days ago
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Xiaoweizi
2
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Is this bear bile acid extracted from bear bile? Can raw materials be synthesized artificially?
Tencent users 19 days ago
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Paranasi
2
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Refuse bear bile pharmaceutical
Tencent users 19 days ago
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sun
four
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If yes, please synthesize.
Tencent users 19 days ago
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Cold and quiet
seven
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Brother Xiong, lie down! ! !
Tencent users 19 days ago
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Xixin smile
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Can't you hurt other animals?
Tencent users 19 days ago
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Blue dolphin
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The poor bear is going to get hurt again! ! ! ...........
Beijing Chaoyang 19 days ago
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User w9jw_oz
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Professor Xu is studying chemical synthesis.
Tencent users 18 days ago
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Will leave Hosta
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It is reported that bile was taken from live bears, which was very cruel. Now, do you want to satisfy all human self-interests at the expense of other species on earth?
Tencent users 18 days ago
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Tencent users
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In the past two years, the vaccine response has been great, and the symptoms of bad liver and gallbladder are obvious. Liver fire is strong, explosive and easy to dry, indigestion. There are several indicators of liver and gallbladder in the physical examination now. Can you take this medicine?
Tencent users 19 days ago
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User c_o9kcr
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How to eat, how much dose to eat.
Tencent users 19 days ago
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follow one's own inclinations
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COVID-19 is not terrible. Improper drug treatment is not worth the loss. Rational thinking is not enough.
Tencent users 18 days ago
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term of endearment
1
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Even if you go all out to develop, you have to spend time in it.
Tencent users 19 days ago
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User u2irkjr
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This is to get a few listed companies.
Tencent users 19 days ago
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Come in suddenly
1
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Where can I buy it? We want to purchase goods.
Tencent users 19 days ago
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The swallow in spring
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I happen to have a box at home. Eat it.
Tencent users 19 days ago