Recently, a study led by the University of Cambridge in the UK found that a commonly used liver drug, ursodeoxycholic acid , can have an impact on the new coronavirus. It reduces the number of ACE-2 receptors on cells, making it more difficult for viruses to enter human cells. In the
experiment, the researchers determined that ursodeoxycholic acid is a drug that can be used to prevent the new coronavirus through the cultured organoids, donor organs, animals and human experiments.
(Source: Nature)
Among them, all 6 untreated hamsters were infected with the new coronavirus, and their weight began to drop after they became ill. Of the 9 animals pretreated with ursodeoxycholic acid, only 3 were infected and had a lower severity.
Then, they infected two donated human lungs with the new coronavirus, and the results showed that the lungs pretreated with ursodeoxycholic acid can significantly resist infection.
Figure | Perfusion of lung (Source: Teresa Brevini)
In subsequent tests, 8 human volunteers received normal doses of ursodeoxycholic acid. Afterward, they underwent a nasal swab test and the results showed a significant decrease in the concentration of ACE2 receptor on nasal epithelial cells.
This means that a way to close the door of the virus was discovered, preventing it from entering human cells from the beginning, thus protecting us from infection.
Because of the treatment method of this drug, it targets human cells, not viruses. Therefore, it is expected to produce similar preventive effects for new variants of the future virus, as well as other coronavirus that may appear.
Figure | Related papers (Source: Nature)
For example, if the virus is the "enemy", whenever we encounter a different "enemy", we must create a "tailored" "weapon" for it, that is, the vaccine . The use of ursodeoxycholic acid is based on our perspective, and by increasing one's own "force" and using the same "move" to eliminate many "enemy" with the same "move".
Professor of Biochemical Engineering at East China University of Science and Technology Xu Jianhe said that Ursodeoxycholic acid (UDCA, ursodeoxycholic acid) is a chiral molecule that is naturally secreted and has physiological activity in the human body, and is a steroidal compound. Although
has a very small amount of secretion in the human body, it has the effect of enhancing liver cell activity and its metabolic function. No reports of toxic side effects on the human body have been seen.
At the same time, ursodeoxycholic acid has also obtained clinical application approval and has been found to have the effects of cholesterol-induced gallbladder stones, cholestatic liver disease, and prevent drug-induced stone formation.
It is also reported that This study led by of the University of Cambridge shows that the reason why the new coronavirus can invade human cells is inseparable from the receptor in the cells, and ursodeoxycholic acid can "lock this door."
If it can be confirmed in larger clinical trials, ursodeoxycholic acid may become an important drug to protect people at high risk of not being vaccinated or vaccinated ineffectiveness.
It is well known that vaccines protect us by strengthening the human immune system, i.e. being able to recognize and clear the virus, or at least weaken it. However, vaccines are not entirely effective for patients with weak immune systems.
And not everyone can get a vaccine. In addition, the virus can also mutate into a new variant to counter the antibodies in the body, and the vaccine effect will be reduced.
And Ursodeoxycholic acid not only protects us from the new coronavirus infection, but also does not rely on the immune system and can complement vaccination.
Close New coronavirus infection this "door"
In the cooperative team led by Cambridge University, a member previously mainly studied organoids, and he used "micro bile ducts" to study bile duct diseases. Another member previously studied the liver, which cultivated micro livers, so-called organoids, to study the development of liver disease, as well as treatment and prevention methods.
When the 2020 new coronavirus SARS-CoV-2 appears, the research team will also turn their attention to this new threat. Later, they found that the liver cells carried a large number of ACE-2 molecules on the surface. This surprised them because it was the receptor for the novel coronavirus. Previously, the research team did not know that the liver would be particularly infected or affected by the new coronavirus.
Using a similar method, the research team accidentally discovered a molecule called FXR (farnesoid X receptor), which is present in large quantities in these bile duct organoids.
They also found that by directly regulating the virus, it can enter the "gate" used by cells, that is, the ACE2 receptor, thereby effectively reducing its existence, just like "closing the door".
Then, they studied how the number of ACE2 receptors on hepatocytes was controlled. An interesting mechanism was found: there is a high concentration of ACE2 receptor in epithelial cells in in the bile duct and gallbladder .
However, if bile acids are not rinsed regularly, they will lose expression of ACE2. When bile acids are omitted in the medium, the cells lose the ACE2 receptor. Therefore, they determined that bile acids could serve as regulators of ACE2 receptors.
And the mechanism behind this is more complicated: bile acids can activate the FXR receptor, and the FXR receptor in turn stimulates the production of ACE2. Without bile acids, the FXR receptor cannot be activated, and there will be no ACE2 receptor.
Similarly, inhibiting bile acids can also reduce the number of ACE2 receptors in the lungs and intestines. Of course, they also want to know whether this correlation also exists in the target tissues of the new coronavirus, namely the lungs and intestines.
In the paper, the researchers said that they also found FXR receptors in organoids produced by lung or intestinal cells, which suggests that bile acids can lead to an increase in FXR receptors, which in turn lead to an increase in ACE2 receptors.
The next question is, can this process also be reversed: that is, can the number of ACE2 receptors be reduced through this pathway?
Fortunately, there are drugs on the market that can reduce the concentration of bile acid in liver diseases. The research team added these substances to different organoids in the liver, lungs and intestines. The results show that the concentration of ACE22 receptor is indeed reduced.
Along this line, they used ursodeoxycholic acid to conduct experiments and found that it can have an effect on FXR and reduce ACE2 receptors in human cells.
In addition, using the same method can also close the ACE2 "gate" of organoid "mini lungs" and "mini intestines". As mentioned earlier, The lungs and intestines are the two main targets of the new coronavirus, so closing this "door" can prevent virus infection.
Figure | Lung Organoids (Source: Teresa Brevini)
was successful in both mouse experiments and human experiments
Next step, it is to prove that this drug can not only prevent infection in laboratory cultured cells, but also prevent infection in organisms.
Experiments have proved that this drug can prevent infection in hamsters exposed to the virus. In the past, this experiment has also been regarded as a "gold standard" model for preclinical testing of anti-COVID drugs.
More importantly, hamsters treated with ursodeoxycholic acid can resist the Delta variant (the latest variant of the new coronavirus during the experiment). At that time, the effectiveness of mainstream vaccines on the virus had been shown to decline.
Next, the research team let the new coronavirus infect the organoids of the liver, lungs, and intestines. These viruses were obtained from the nasal swabs of infected patients. For some of these organoids, ursodeoxycholic acid was used for pretreatment; while others did not.
Figure | Biliary duct/hepatic organoids treated with ursodeoxycholic acid and exposed to SARS-CoV-2, red indicates virus (Photo source: Teresa Brevini)
Results show that this drug will cause a sharp drop in the infection rate. The ACE2 receptors in the nasal, lung, liver, and intestinal epithelial cells of mice and hamsters who took the drug were also significantly reduced.
That is to say, this drug can protect hamsters from virus infection, proving that it can indeed effectively prevent infection.
Of course, the research team wants to show this in humans more than hamsters. Later, they studied donated lungs. The two lungs are perfused with drugs to be able to check the effects of the drugs on the same organ. They gave one lung perfusion treatment standard concentration and another lung perfusion placebo.
The ACE2 levels of the two lungs were the same at the beginning of the experiment, and then changed, and the number of ACE2 receptors in the perfused lungs decreased sharply.
The concentration of ACE2 is also lower in the serum of patients with congenital liver disease who have been taking this drug for a long time than those who have not taken this drug.
This discovery may also be important for organ transplantation, considering the risk of the spread of the new coronavirus through the transplanted organ, this may help with drug treatment before organ transplantation.
A low-cost, low-side effects new crown drug is expected to be born
Researchers pointed out that although appropriate control randomized trials are needed to confirm these findings. However, the evidence provided by experimental data is convincing that ursodeoxycholic acid can be used as a drug to prevent the new coronavirus and assist vaccination, especially among vulnerable groups.
Since it targets the ACE2 receptor directly, they hope it can have an effect on the evolution of the new coronavirus synapses, thus coping with the possible viral mutation .
It can be said that the biggest challenge in developing intervention measures for the new coronavirus is the continuous emergence of new viral mutations. This discovery has brought real progress to a low-cost, safe and universal treatment method, and has also given humans a new potential method to fight the current and future COVID-19 infections. In the
, the research team used all the methods that could be thought of to prove that ursodeoxycholic acid can indeed keep the virus out and thus protect us from the new coronavirus. More importantly, the drug works on our cells, so it is not affected by viral mutations, and it may be effective even if new mutant strains appear.
At the same time, this is an "affordable and effective" way. Ursodeoxycholic acid has been used clinically for many years, and it has been proved that it is not only safe, but also very tolerated, so it can be used directly for people at high risk of the new coronavirus.Unlike viruses, the body's own ACE2 receptor does not change, so the risk of developing drug resistance is smaller.
At the same time, this drug is cheap, can be mass-produced, easy to store or transport, and can be deployed quickly and conveniently. Researchers even optimistic that the drug may become an important weapon in the fight against the new crown epidemic.
Of course, appropriate clinical trials are needed to verify this hope. But if successful, a low-cost, low-side effects drug will be born and will be quickly popularized around the world.
Xu Jianhe analyzed that it may still take a long time before ursodeoxycholic acid is truly launched into the market and becomes a new crown-related drug. Although there are already relevant ursodeoxycholic acid tablet preparations, its indications are not diseases caused by the new crown, so it still needs to start with clinical trials as a new crown drug.
"However, compared with clinical trials of new drugs, the phase I clinical trials of drug safety and reliability may be accelerated. At present, more clinical trials are mainly needed to reveal whether they have the actual effect of preventing and treating symptoms of COVID-19," said Xu Jianhe.
Xu Jianhe: Start the artificial synthesis of ursodeoxycholic acid, and take a different approach to save Black bear
In fact, Xu Jianhe and his team began to study the enzymatic synthesis of ursodeoxycholic acid as a chiral molecule ursodeoxycholic acid from around 2012.
Figure | Xu Jianhe (Source: Xu Jianhe)
He said: "I accidentally saw news reports that the source of ursodeoxycholic acid still relies on the live bear bile extraction technology criticized by the international community. So I immediately decided to start the research on artificial synthesis methods. The original intention at that time was to find a different approach to save black bears."
"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 ; and transforming the production method of ursodeoxycholic acid from animals to green and efficient biosynthesis is also the mission and charm of synthetic biology." Xu Jianhe added.
At present, Xu Jianhe's team and Baifuan Biotechnology Company are using synthetic biology and a new generation of multi-enzyme cascade catalytic technology to synthesize key functional molecules that are useful clinically or industrially but difficult to obtain on a large scale.
"One of the important application directions is chiral medical raw materials and their key intermediates, and ursodeoxycholic acid is one of our representative products." Xu Jianhe finally said.
Support: Ren, Bao
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