Previous research on COVID-19 specific drugs and vaccines has been developed for the virus itself. As the virus changes and evolves faster, these treatments have become less effective, and they have even become "exclusive versions" of specific variants.
At present, a generic drug targeting the coronavirus entering the cellular path is expected to break through this dilemma and achieve "unchanged responding to all changes" in the prevention of novel coronavirus infection.
On December 5,2022, researchers at the University of Cambridge published a research paper on Nature called FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2.
The results prove two things: FXR can control ACE 2 expression; blocking this pathway helps to reduce novel coronavirus infection. The generic drug, ursodeoxycholic acid, which was used in the trial, once became a hot topic.
The angiotensin converting enzyme 2 (ACE 2) receptor is expressed on the surface of many cells, and the novel coronavirus binds to ACE 2 through the spike protein on the surface to enter the cells to achieve infection. Because this receptor is abundant on cholangiocytes, novel coronavirus can also cause abnormal liver function.
In various tissues affected by novel Coronavirus, including the gastrointestinal and respiratory systems, the researchers confirmed that FXR is a direct regulator of ACE 2 transcription, as well as ursodeoxycholic acid, the drug for gallstones and liver diseases. As an FXR inhibitor, it can inhibit the expression of ACE 2 receptors on cholangiocytes by inhibiting the transcription factor FXR.
In the preclinical trial, nine hamsters were given a dose of ursodeoxycholic acid similar to those used in humans; and six other hamsters were given a saline solution. A week later, the hamsters were placed in the same home cage as those infected with the Delta coronavirus variant.
The hamsters were euthanized after 4 days later. The study team analyzed their lung samples. Of these, all of the hamsters receiving saline injections were infected with the virus, but only 1 / 3 of those receiving ursodeoxycholic acid treatment were infected with the virus.
Hamsters had free access to food during the trial. However, the hamsters in the saline group had lost about 9% of their body weight on day 4 after the virus infection; by contrast, those in the ursodeoxycholic acid group had increased their body weight. This suggests that the severity of novel coronavirus has decreased even after treatment with ursodeoxycholic acid.
In other words, it's hard to say that ursodeoxycholic acid prevents 100% of the virus from entering the cells, but it largely prevents the virus from entering the cells and reduces the disease.
Next, the research team tested the efficacy of ursodeoxycholic acid treatment in lung tissue donated by volunteers. These lung tissues maintain physiological function through in vitro support such as ventilator.
The researchers injected ursodeoxycholic acid into one lung, while the other lung was injected with saline.
After 6 hours, the ACE 2 expression levels decreased by nearly 50% in the ursodeoxycholic acid-treated lungs, but not in the control lungs. The results showed that the lungs of the injection were not infected by the novel coronavirus, while the other lung was infected with the novel coronavirus.
In eight healthy subjects, the investigators also observed reduced ACE 2 expression levels in nasal cells of volunteers receiving ursodeoxychic acid.
It is noteworthy that neither hamsters nor lung organ donors have low immunity. However, compared with the COVID-19 vaccine, drugs such as ursodeoxycholic acid may be more suitable for people with lower immunity due to different mechanisms.
Previously, these groups with low immunity and an inability to use the COVID-19 vaccine could use Astrazeneca's neutralizing antibody Evusheld to prevent the novel coronavirus infection. Evusheld By binding to different sites on the Novel Coronavirus spike protein, thus reducing the ability of the virus to enter and infect healthy cells. In July this year, the drug for the first time in the Chinese mainland access —— can be used in the Hainan Boao Lecheng International Medical Tourism Pilot Zone.
However, the good times did not last long, the virus evolved rapidly, and the spike protein composition of the new variant was changed, which reduced the efficacy of Evusheld. This also reflects that if the drug is designed by the virus, it will be in a passive state.
ACE 2 is the door for the virus to enter, and if it is closed, it means that the virus cannot replicate itself, that is, in the battle against novel coronavirus, a method without relying on the immune system can be used to prevent infection.
So, can ursodeoxycholic acid replace vaccination? The researchers responded that the vaccine is currently the best possible way to prevent the novel coronavirus infection today, but that it could complement each other and reduce the risk of infection.
Currently, researchers are moving ahead with the launch of clinical trials to determine whether the effect of ursodeoxycholic acid in animals and organoids can be applied to the real world.
