Ursodeoxycholic acid, regaining the initiative from coronavirus prevention

Previous research on new crown drugs and vaccines has mostly been developed for the virus itself. As the virus mutates and evolves faster, the efficacy of these treatments becomes worse and worse, and even becomes the "exclusive version" of specific variants and is withdrawn.

At present, a generic drug for coronavirus to enter the cell pathway is expected to break through this dilemma and achieve "unchanged response" in the prevention of new coronavirus infection.

On December 5, 2022, researchers from the University of Cambridge in the United Kingdom published a research paper in Nature called FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2.

The results proved two things: FXR could control ACE2 expression; Blocking this pathway is conducive to reducing new coronavirus infections. The generic drug ursodeoxycholic acid used in the trial once became a hot topic.

Angiotensin-converting enzyme 2 (ACE2) receptors are expressed on the surface of many cells, and the new coronavirus binds to ACE2 through the spike protein on the surface, thereby entering cells to achieve infection. Because this receptor is abundant in the expression of bile duct cells, the new coronavirus can also cause abnormal liver function.

In a variety of tissues affected by the new coronavirus, including the gastrointestinal and respiratory systems, the researchers confirmed that FXR is a direct regulator of ACE2 transcription, and the drug ursodeoxycholic acid for the treatment of gallstones and liver diseases, as an FXR inhibitor, can inhibit the expression of ACE2 receptors on cholangiocyte cells by inhibiting transcription factor FXR.

In preclinical trials, researchers gave nine hamsters a similar dose of ursodeoxycholic acid as humans; Another six hamsters were given saline solutions. A week later, the hamsters were placed in the same cages as hamsters infected with the Delta coronavirus variant.

After 4 days, the hamsters were euthanized. The team analyzed samples from their lungs. Of these, all hamsters who received saline injection were infected with the virus, but only 1/3 of hamsters treated with ursodeoxycholic acid were infected with the virus.

During the trial, hamsters were free to get food. However, hamsters in the saline group lost about 9% of their weight on day 4 after infection; In contrast, hamsters in the ursodeoxycholic acid group gained weight. This suggests that after receiving ursodeoxycholic acid treatment, even if infected with the new coronavirus, its severity is reduced.

In other words, it is difficult to say that ursodeoxycholic acid can prevent 100% of the virus from entering the cell, but it can largely prevent the virus from entering the cell and alleviate the disease.

Next, the research team tested the treatment effect of ursodeoxycholic acid in lung tissue donated by volunteers. These lung tissues maintain physiological function through extracorporeal support such as ventilators.

The researchers injected ursodeoxycholic acid into one lobe of the lung, and the other lobe was injected with normal saline.

After 6 hours, ACE2 expression levels in ursodeoxycholic acid-treated lungs decreased by nearly 50%, but there was no change in the control group. The results showed that the lung that injected the drug was not infected by the new coronavirus, while the other lobe lung was infected with the new coronavirus.

In 8 healthy subjects, the researchers also observed reduced levels of ACE2 expression on nasal cells in volunteers who received ursodeoxycholic acid.

It is worth noting that neither hamsters nor lung organ donors have low immunity. However, compared with the new crown vaccine, drugs such as ursodeoxycholic acid may be more suitable for people with low immunity due to different mechanisms.

Previously, these groups with low immunity and no access to the new crown vaccine could use AstraZeneca's neutralizing antibody Evusheld to prevent new crown virus infection. Evusheld reduces the virus's ability to enter and infect healthy cells by binding to different sites on the coronavirus spike protein. In July this year, the drug was admitted to the Chinese mainland for the first time in the first pilot - it can be used in the Boao Lecheng International Medical Tourism Pilot Zone in Hainan.

But the good times did not last long, the virus evolved rapidly, and the composition of the spike protein of the new variant changed, making Evusheld less effective. This also reflects that if the drug is designed according to the virus, it is bound to be in a passive state.

ACE2 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 the new coronavirus, an approach that does not rely on the immune system can be used to prevent infection.

So, can ursodeoxycholic acid replace vaccination? The researchers responded that vaccines are the best way to prevent new coronavirus infections today, but the two can complement each other and reduce the risk of infection.

Currently, the researchers are advancing the initiation of clinical trials to determine whether the effects of ursodeoxycholic acid in animals and organoids can be applied to the real world.