Although they can be highly effective, current methods of preventing and treating COVID-19 infections suffer from a fatal flaw, said Teresa Brevini, a biologist in the United Kingdom who recently completed her PhD at the University of Cambridge. “Vaccines, monoclonal antibodies and antivirals work on the virus, and unfortunately, as we’ve seen, this virus is quite intelligent and can mutate,” Brevini told the Daily Beast. She is the first author of a new study on ursodeoxycholic acid, or UDCA, for the prevention of COVID. Importantly, rather than acting on the virus, UDCA modifies human cells to prevent the virus from infecting them. “If we just shut the door on the virus, it really can’t do anything,” Brevini said. The research by Brevini and her colleagues was published in the journal Nature on Monday. UDCA “closes the door” on COVID by reducing the amount of a receptor called ACE2 on the surface of cells. ACE2 normally controls blood pressure and limits organ damage, but in a twist of fate, it also makes the perfect docking station for the SARS-CoV-2 spike protein. When the virus infects cells in a person’s respiratory tract, it uses ACE2 receptors like doors. “If we just shut the door on the virus, it really can’t do anything.” Teresa Brevini In the early months of the pandemic, Brevini and her lab were working remotely during the lockdown when they noticed a quirk in some of their liver cells. “We were all at home, checking some of our data on the computer, and we said, ‘Wait—ACE2, the door that the virus uses, is expressed in our cells,’” Brevini said. Not only that, the researchers inadvertently increased the number of ACE2 receptors in some of their liver cells. Brevini said the next scientific hypothesis came naturally to her and her team: “If we have a way to increase the receptor that’s on the cell—so how sensitive the cells can be to the virus—maybe we can use the same mechanism to reduce the amount of the receptor’. She and her co-authors began to pull at this thread by testing UDCA in cultured groups of gallbladder, lung, and intestinal cells and determining that it reduced ACE2 levels in all three cell types. Then, infection of these cell masses with SARS-CoV-2 significantly reduced the amount of viral genetic material compared to clusters that had not received the drug. They repeated this experiment in mice and hamsters before moving to a pair of human lungs on a mechanical ventilator. This place, Brevini said, was “like Frankenstein.” “You see the lungs outside the body, and there’s a ventilator, and you see them inflate and deflate. My mind was blown to see this experiment,” he said. The researchers split the lungs in half and gave one lung UDCA while using the other as a control. After six hours, three areas in the treated lung had cells with fewer ACE2 receptors than in the untreated lung, and these areas were then less susceptible to viral infection. Most experimental treatments need years of clinical study before they become a live human, but UDCA is already widely prescribed to treat cholestatic liver disease. By comparing COVID-19 infection data of patients with chronic liver disease who either received UDCA or not, Brevini and her colleagues were able to analyze the results of a natural experiment. They found that patients on UDCA had a 46% reduced chance of contracting COVID-19. When they did become infected with the virus, they were less likely to develop moderate, severe or critical forms of the disease compared to patients with liver disease who did not take the drug. “We think you could take it prophylactically to reduce the chances of that particular virus infecting your cells.” Teresa Brevini Finally, eight healthy volunteers agreed to take UDCA in pill form for five days. The researchers measured ACE2 levels in their noses with daily nasopharyngeal swabs, finding reduced levels of the receptors even within days. Brevini said this finding makes her hopeful that one day, the pill could be used as a way to reduce the risk of infection, with or without exposure. “Say you’re having lunch with your colleague one day and then the next day he texts you ‘I’m so sorry, I’ve got COVID,’” Brevini said. “If you’ve had your shot, you’re protected in that regard, but is there anything more you can do? We think you could take it prophylactically to reduce the chances of that particular virus infecting your cells.” “It’s remarkable that a safe and available drug” might be able to prevent COVID-19 infections, Stuart Lipton, a molecular medicine researcher at the Scripps Research Institute who was not involved in the study, told The Daily Beast. “The drug certainly warrants further testing” in a randomized and long-term human clinical trial, he added. Even so, Lipton cautioned that UDCA can have unwanted side effects on a person’s blood pressure and kidney function, which can happen when the number of ACE2 receptors in a cell is reduced. “I am concerned that widespread use of the drug may reveal serious and unwanted side effects, especially in vulnerable, elderly populations who would be most in need of drug therapy,” he said. Other groups of researchers are working on ways to reduce ACE2 receptors only in cells that are vulnerable to SARS-CoV-2 infection, in the respiratory tract and lungs. Lipton led a study published in Nature Chemical Biology in September and found that a targeted method of blocking ACE2 reduced the virus’s ability to infect human cells and hamsters. What these methods have in common is a promising tactic to fight this virus that we’ve had in our arsenal ever since: slamming the doors on our cells and preventing infection in the first place.
