With successive waves of uncapping, enhancing disease resistance has become one of the most important things at present. Vaccines are the most effective medicines to fight the coronavirus at the moment, and intensified vaccination is also a more desirable method.

 

However, the Omicron virus strain has evolved an extreme ability to infect, and it is not realistic to hope for a vaccine to eliminate the infection. On the other hand, the harm to the elderly and children of Omicron remains non-negligible, and these two groups are, in turn, precisely the less immunocompromised groups, for whom vaccination may be less effective than in healthy adults. Protection for there is very necessary, and also subject to additional measures.

 

In fact, the rationale is consistent whether it is Omicron, or a previous variant strain such as Delta that infects the human body, that is, using the “keys” they carry to open the “door” of the cells, which in turn enables infection and dissemination.

 

This “key” is the spike protein of the coronavirus, and the “door lock” is angiotensin-converting enzyme 2 (ACE2) on the surface of human cells. As the virus mutates, the “key” increasingly adapts to the “door lock” to such an extent that transmissibility is continuously enhanced.

If ACE2 could be decreased, or otherwise blocked, which means blocking the binding of viral spike proteins and ACE2, it would not be possible to “unlock” ACE2 into the cell regardless of how the virus evolved. Thankfully, this wonderful idea seems just to be realized!

 

On December 5, Nature published a paper in which the research team said they had discovered drugs that block ACE2, and that was the common, odd old drug, ursodeoxycholic acid.

 

Ursodeoxycholic acid was originally obtained from an in vivo extraction from bears and nowadays can already be produced artificially. It is widely used in the treatment of hepatobiliary diseases and has a choleretic function.

 

The team had made the unexpected discovery that bile acids could elevate ACE2 expression, with the principle that bile acids activate the FXR pathway and that FXR binds to the ACE2 gene promoter site to drive ACE2 transcription. FXR is widely distributed in the airways and intestines, which are also the sites of susceptibility to infection by SARS-CoV-2.

 

Next, the researchers stimulated airway and intestinal organoids with bile acids, then FXR and ACE2 levels were definitely elevated. And treatment with ursodeoxycholic acid could decrease the FXR and ACE2 content. Meanwhile, they also found that ursodeoxycholic acid could reduce the infection rate of SARS-CoV-2 in both in vitro and animal experiments.

 

These basic experimental results give researchers confidence. So, they further utilized human organs for research. Because ethical limitations preclude performing experiments directly in humans, the experimenters chose two healthy human donor lungs that had not been used for organ transplantation, one perfused with ursodeoxycholic acid and the other as a control.

 

 

As envisaged, lung tissue had significantly lower ACE2 content after ursodeoxycholic acid treatment. Infection of lung tissue with the SARS-CoV-2 after perfusion with ursodeoxycholic acid showed that ursodeoxycholic acid greatly reduced the extent of infection in the lung tissue.

 

To this point, the experimental team applied for further studies in clinical. They recruited eight healthy volunteers to use a conventional therapeutic dose of ursodeoxycholic acid for five consecutive days and then swabbed with a cotton stick to obtain nasal mucosal epithelial cells of the subjects for detection.

 

Unsurprisingly, after ursodeoxycholic acid treatment, ACE2 was significantly decreased in the nasal mucosal epithelia of the subjects. In addition, they collected information on serum proteins from clinical patients, a subset of whom had used ursodeoxycholic acid. Correlation analysis suggested that patients treated with ursodeoxycholic acid had lower serum ACE2 levels, which is in agreement with previous experimental conclusions.

 

To further verify whether ursodeoxycholic acid protects against SARS-CoV-2 infection, the investigators analyzed the relevant clinical data. The results showed that among patients infected with SARS-CoV-2, the group using ursodeoxycholic acid had a better prognosis, shorter hospital stay, and lower rates of critical illness and mortality.

 

So, can ursodeoxycholic acid work synergistically with vaccines? They found significantly lower rates of moderate to severe illness in groups that had been vaccinated and used ursodeoxycholic acid.

 

Although there have been no clinical trials to confirm the efficacy of ursodeoxycholic acid in the treatment of SARS-CoV-2, this result undoubtedly gives us new hope. Ursodeoxycholic acid is widely purchased, inexpensive, and has fewer side effects, making it more suitable for use by the general population than the so-called COVID19 specific medicine.

 

But at the same time, we should also note that this is still only a basic study, and how exactly ursodeoxycholic acid works needs more attention. As the SARS-CoV-2 continues to mutate, it is also unknown whether the virus will open pathways other than ACE2 to infect the human body and everything still needs to be treated with caution and closely monitored.

 

Reference

Brevini T, et al. FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2. Nature. 2022 Dec 5. doi: 10.1038/s41586-022-05594-0.