Previous research on specific drugs and vaccines for COVID-19 has mostly focused on the virus itself. With the rapid mutation and evolution of the virus, the efficacy of these treatments became worse and worse, and they even became "exclusive versions" of specific variants and were withdrawn from the market.
Now, a generic drug targeting the pathway of the coronavirus into cells is expected to break through this dilemma, realizing "the same as the same" in the prevention of the novel coronavirus infection.
On December 5, 2022, researchers from the University of Cambridge in the UK published a research paper entitled FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2 in Nature.
The results showed two things: FXR can control ACE2 expression; Blocking this pathway will help reduce COVID-19 infections. Ursodeoxycholic acid, the generic drug used in the trial, was the subject of much debate.
Angiotensin-converting enzyme 2 (ACE2) receptors are expressed on many cell surfaces, and the novel coronavirus binds to ACE2 through surface spike proteins, thus entering cells and infecting them. Because this receptor is highly expressed in bile duct cells, the novel coronavirus can also cause liver dysfunction.
In a variety of tissues affected by COVID-19, including the gastrointestinal and respiratory systems, researchers have demonstrated that FXR is a direct regulator of ACE2 transcription, as well as ursodeoxycholic acid for the treatment of gallstones and liver disease. As an FXR inhibitor, FXR inhibits ACE2 receptor expression on bile duct cells by inhibiting the transcription factor FXR.
In preclinical trials, researchers gave nine hamsters ursodeoxycholic acid at a dose similar to that of humans; Six other hamsters were given a saline solution. A week later, the hamsters were placed in the same cage as hamsters infected with the Delta coronavirus variant.
The hamsters were euthanized four days later. The team analyzed their lung samples. All of the hamsters that received saline were infected, but only a third of those that received ursodeoxycholic acid were infected.
During the experiment, the hamsters were given free access to food. But the saline hamsters lost about 9 percent of their body weight on the fourth day after infection; In contrast, the hamsters in the ursodeoxycholic acid group gained weight. This suggests that ursodeoxycholic acid treatment can reduce the severity of COVID-19 infection.
In other words, it's hard to say that ursodeoxycholic acid can block the entry of the virus 100% of the time, but it can block the entry of the virus and reduce the disease to a large extent.
Next, the team tested ursodeoxycholic acid treatment on lung tissue donated by volunteers. These lung tissues maintain their physiological functions through extracorporeal support such as ventilators.
The researchers injected ursodeoxycholic acid into one lung and saline into the other.
After six hours, the ursodeoxycholic acid-treated lungs showed a nearly 50 percent reduction in ACE2 expression, but there was no change in the control lungs. The results showed that the lung injected with the drug was not infected with the virus, while the other lung was.
In eight healthy subjects, the researchers also observed reduced levels of ACE2 expression on nasal cells in the volunteers who received ursodeoxycholic acid.
Notably, neither the hamsters nor the lung organ donors were immune compromised. But compared with the COVID-19 vaccine, drugs like ursodeoxycholic acid may be better suited to people with lower immunity due to their different mechanisms.
Astrazeneca's neutralizing antibody Evusheld was previously used to prevent COVID-19 infection in those with low immunity and unable to use COVID-19 vaccines. Evusheld reduces the virus's ability to enter and infect healthy cells by binding to different sites on the coronavirus spike protein. In July, the drug was approved for the first time on the Chinese mainland on a pilot basis -- it can be used in the Boao Lecheng International Medical Tourism Pilot Zone in Hainan.
But that didn't last long. The virus evolved rapidly and the new variant changed the composition of the spike protein, making Evusheld less effective. This is also a side effect, if the drug is designed for the virus, it will be passive.
ACE2 is a gateway for viruses to enter, and closing it means that the virus cannot replicate itself, which means that there is a way to prevent infection that does not depend on the immune system in the battle against the novel coronavirus.
So could ursodeoxycholic acid replace vaccination? Researchers responded that vaccines are currently the best way to prevent COVID-19 infection, but the two can complement each other to reduce the risk of infection.
The researchers are now moving forward with clinical trials to determine whether the ursodeoxycholic effect in animals and organoids can be applied in the real world.
