Nature: Significant progress! Ursodeoxycholic acid, which was originally used to treat liver disease, is expected to be used to prevent new coronavirus infection

In a new study, researchers from research institutions such as the University of Cambridge in the United Kingdom and the Charité Inky in Berlin, Germany, looked at miniature organs, donor organs, animals and patients, and found that a drug whose patent protection has expired could be repurposed to prevent COVID-19 and may be able to protect against future variants
of the coronavirus SARS-CoV-2 that causes the disease 。 The results of the study were published online on December 5, 2022 in the journal Nature under the title "FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2.
"

The new study points to an existing drug used to treat a certain liver disease that "locks" SARS-CoV-2's gateway into our cells, the receptor ACE2
on the cell surface.
Because the drug targets host cells rather than viruses, it should be able to protect against future new variants of SARS-CoV-2 as well as other coronaviruses
that may emerge.
If confirmed in larger clinical trials, this would provide an important drug
for protecting those whose vaccines are ineffective or unavailable, as well as those at increased risk of infection.

Dr Fotios Sampaziotis, co-corresponding author of the paper and the University of Cambridge, said: "Vaccines protect us by boosting our immune system, enabling it to recognize the virus and clear it, or at least weaken it
.
But vaccines are not effective for everyone--- such as those with weakened immune systems--- and not everyone has access to them
.
In addition, SARS-CoV-2 has been mutated to produce new anti-vaccine variants
.
We are interested in finding other ways to protect us from SARS-CoV-2 infection that do not rely on the immune system and may be able to serve as a remedy
for vaccination.
We have found a way to close the portal for this virus to enter our cells, thus preventing it from entering our cells in the first place, protecting us from infection
.
”

Dr.
Sampaziotis has previously been studying bile duct disease
with organoids --- "miniature bile ducts" ---.
Organoids are a group of cells that can grow and proliferate when cultured in vitro, presenting a three-dimensional structure
with the same function as the part of the organ being studied.

Based on this, the authors quite accidentally discovered that a molecule called FXR, which is abundant in bile duct organoids, directly regulates the gateway for SARS-CoV-2 into host cells: ACE2, which effectively turns it
on and off.
They went on to discover that ursodeoxycholic acid (UDCA), a patent-expired drug used to treat a liver disease called primary biliary cholangitis, "turned off" FXR, thus closing the ACE2 portal
.

In the new study, the authors found that they could use the same method to close the ACE2 portal in the "mini-lung" and "mini-guts" and prevent SARS-CoV-2 infection
.

The next step is to show that the drug can prevent infection
not only in lab-grown cells, but also in organisms.
To this end, they collaborated with Professor Andrew Owen of the University of Liverpool to find that the drug was able to prevent infection in hamsters exposed to the SARS-CoV-2 virus, which is used as a "gold standard" animal model
for preclinical testing of anti-SARS-CoV-2 drugs.
Importantly, hamsters treated with UDCA were protected from the then-emerging SARS-CoV-2 variant Delta
, which was partially resistant to existing vaccines.

Suppression of FXR in vitro reduces ACE2 levels in human lungs and SARS-CoV-2 infection
.
Image from Nature, 2022, doi:10.
1038/s41586-022-05594-0.

Professor Owen, "Although we need appropriately controlled randomised trials to confirm these findings, these data provide compelling evidence that UDCA has the potential as a drug to protect people from SARS-CoV-2 and as a remedy for vaccination, particularly in
vulnerable populations.
" Given that it targets the ACE2 receptor directly, we hope that it may be more resilient to changes resulting from the evolution of the SARS-CoV-2 spike protein, which can lead to the rapid emergence
of new variants.
”

Next, the authors teamed up with Professor Andrew Fisher of Newcastle University and Professor Chris Watson of Aidenbrook Hospital to see if their findings in hamsters apply to human lungs
exposed to the virus.

The authors took a pair of donor lungs that were not suitable for transplantation, let them breathe outside the body on a ventilator, and used pumps to circulate blood-like fluids in their bodies to keep the lung organs functioning, while they could be studied
.
One donor lung was given the drug, but both donor lungs were exposed to
SARS-CoV-2.
Sure enough, the lung of the donor given the drug was not infected, while the lungs of the other donor were infected
.

Professor Fisher said, "This is one of the first studies to test the effect of
a drug when perfused throughout a human organ.
This may be important for organ transplantation--- given the risk of spreading COVID-19 through transplanted organs, it may open up the possibility of
treating organs with drugs to clear the SARS-CoV-2 virus before transplantation.
”

Next, the authors collaborated with Professor Ansgar Lohse of the University Medical Center Hamburg in Germany to conduct a study
of human volunteers.

Professor Lohse explains, "We recruited 8 healthy volunteers to receive the drug
.
When we wiped the noses of these volunteers with cotton swabs, we found lower ACE2 levels, suggesting that the virus had less chance of entering and infecting their nasal cells, which are the main channel
for this virus.
”

While it was not possible to conduct a full-scale clinical trial, the authors did a suboptimal thing: look at COVID-19 outcome data from two separate cohorts of patients, comparing
those already taking UDCA for liver disease to those who did not.
They found that patients treated with UDCA were less likely to develop severe COVID-19 and be hospitalized
.

A safe, affordable drug that fights against the SARS-CoV-2 variant

Lead author Teresa Brevini, a PhD student at the University of Cambridge, said: "This unique study gives us the opportunity to do true translational science, using laboratory discoveries to directly address clinical needs
.
Using almost all the methods at hand, we found that an existing drug that shuts down the ACE2 portal for this virus to enter cells can protect us from COVID-19
.
Importantly, because the drug works on our cells, it is not affected by viral mutations and should be effective
even as new variants emerge.
”

Dr.
Sampaziotis said the drug could be an affordable and effective way to
protect those whose COVID-19 vaccines are ineffective or unavailable.
"We've been using UDCA clinically for years, so we know it's safe and very well tolerated, which allows people at high risk of COVID-19 to use it
directly.
" The drug is low-cost, can be produced quickly and in large quantities, and is easy to store or transport, making it easy to deploy quickly in outbreaks--- especially against variants of resistance vaccines, when it may be the only line
of protection while waiting for a new vaccine to be developed.
We are optimistic that this drug could become an important weapon
in our fight against COVID-19.
(Biovalley Bioon.
com)

Resources:

Teresa Brevini et al.
 FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2.
Nature, 2022, doi:10.
1038/s41586-022-05594-0.