An impressive new study published in Nature is pointing to a new kind of treatment to protect the vulnerable from COVID-19. The research revealed an old drug derived from bear bile and used for liver disease can block a crucial pathway used by SARS-CoV-2 to enter human cells.
The research, a collaboration between scientists at the University of Cambridge and the Berlin Institute of Health at Charité, was aimed at developing novel prophylactic treatments for COVID-19. As co-author Fotios Sampaziotis explained, vaccines are a crucial tool but not the only way we can try to stop SARS-CoV-2 infections.
"… vaccines don't work for everyone – for example, patients with a weak immune system – and not everyone have access to them," said Sampaziotis. "We're interested in finding alternative ways to protect us from SARS-CoV-2 infection that are not dependent on the immune system and could complement vaccination."
The origins of the new study go back to the beginning of the pandemic. Early in 2020, researchers quickly homed in on the strategy SARS-CoV-2 employs to enter human cells. Much like its predecessor SARS, this novel coronavirus enters human cells through a doorway called ACE2.
ACE2 is an enzyme that can be found on the surface of cells across much of the human body. And the prolific nature of these ACE2 receptors is a key reason COVID-19 is much more than a simple respiratory disease. ACE2 receptors are particularly prominent in the gut and cardiovascular system, meaning SARS-CoV-2 can strike a variety of locations in the body beyond just the lungs.
One curious finding, from the initial stages of the pandemic, was the dramatic variation in ACE2 levels between different kinds of bile tissue. These early observations suggested some kind of factor, potentially bile acids, seemed to be suppressing the expression of ACE2 in certain cells.
The first big breakthrough came when it was discovered a bile acid molecule dubbed FXR seemed to play a fundamental role in controlling the expression of ACE2. The next big discovery came with the identification of ursodeoxycholic acid (UDCA), a clinically approved liver disease drug, effectively suppressing FXR activity and subsequently lowering ACE2 levels on lab-grown cells.
The foundations for the research at this stage were strong, but the big question was whether UDCA treatment actually reduced volumes of ACE2 receptors in humans. In an article for The Conversation, Sampaziotis and colleague Teresa Brevini detailed the next step in the compelling research.
"We recruited eight healthy volunteers, gave them UDCA, and then swabbed their noses," Brevini and Sampaziotis explain. "We observed a reduction of ACE2 in their nasal cells, the main point of entry for the virus into the body, suggesting SARS-CoV-2 would have fewer opportunities to infect these cells."
The final piece in the puzzle was an epidemiological survey of patients taking UDCA for liver disease. If the drug was at all helpful in reducing the impact of COVID then there should be signs of that in clinical data. And indeed those signs were there, with chronic liver disease patients taking UDCA showing lower rates of COVID hospitalization and death compared to matched control patients not receiving UDCA.
Andrew Owen, a University of Liverpool researcher working on the project, is cautious to stress the need for larger clinical trials before concluding UDCA can be effective against COVID.
"Although we will need properly-controlled randomized trials to confirm these findings, the data provide compelling evidence that UDCA could work as a drug to protect against COVID-19 and complement vaccination programs, particularly in vulnerable population groups," Owen said. "As it targets the ACE2 receptor directly, we hope it may be more resilient to changes resulting from the evolution of the SARS-CoV-2 spike, which result in the rapid emergence of new variants."
This research is far from the first to consider targeting ACE2 as a way of preventing or treating COVID. Several strategies are in various stages of research, from creating decoy ACE2-like molecules that attract SARS-CoV-2 to designing small molecules that bind with ACE2 receptors and block the virus from entering human cells.
What makes this new work particularly novel is its discovery of a common, cheap, pre-existing drug that seems to effectively target ACE2 receptor activity.
Ursodeoxycholic acid was first identified in bile from bears. As a traditional medicine, the use of bear bile to treat a variety of ailments goes back hundreds of years. In the 1950s scientists developed effective ways to synthesize UDCA, the main therapeutic agent in bear bile, reducing the need for harmful bear bile farms.
By the late 1980s the US Food and Drug Administration (FDA) formally approved synthesized UDCA as a drug treatment for liver disease. Since then the drug has moved off-patent and is now accessible as a cheap generic medication.
Sampaziotis is hopeful further clinical testing for UDCA is effective as the drug is known to be safe, well-tolerated and could be easily administered as a prophylactic to patients vulnerable to COVID-19. UDCA may not be the most optimized ACE2-targeting COVID treatment but it could be a valuable stop-gap as we wait for more effective drugs to be developed in the future.
"This tablet costs little, can be produced in large quantities fast and easily stored or shipped, which makes it easy to rapidly deploy during outbreaks – especially against vaccine-resistant variants, when it might be the only line of protection while waiting for new vaccines to be developed," Sampaziotis added. "We are optimistic that this drug could become an important weapon in our fight against COVID-19."
The new study was published in Nature.
Source: University of Cambridge
