Our next best COVID medicine has been hiding in plain sight

The fight against COVID seems to have fallen into a ping-pong rhythm at this point, where every step forward seems undermined by a step back. Vaccines are available and hospitalization rates have fallen dramatically from previous peaks. But only a small number of eligible Americans have received the most recent bivalent vaccine, and the specter of a new, somehow worse variant looms in our collective psyche. Elsewhere, like China, we appear to be losing ground to the virus: a less effective vaccine, coupled with low vaccination rates, limited natural immunity and dissatisfaction with a national Zero-COVID policy, could be catastrophic within weeks. coming. But amid this stalemate, scientists may have found a drug that will decisively bring the battle back to humanity’s side. And the best part is that people have already been prescribed this drug for over 30 years.

While they can be highly effective, our current methods of preventing and treating COVID-19 infections all suffer from a fatal flaw, said Teresa Brevini, a British biologist who recently completed her PhD at the University of Cambridge.

“Vaccines, monoclonal antibodies and antivirals all act on the virus, and unfortunately, as we have seen, this virus is quite intelligent and it can mutate,” Brevini told The Daily Beast. She is the first author of a new study on ursodeoxycholic acid, or UDCA, to prevent COVID. Importantly, instead of acting on the virus, UDCA modifies human cells to prevent the virus from infecting them. “If we just close the door to the virus, it really can’t do anything,” Brevini said.

Research by Brevini and his colleagues has been published in the journal Nature In Monday.

UDCA “closes the door” to COVID by decreasing 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 is also the perfect docking station for the spike protein SARS-CoV-2. When the virus infects cells in a person’s airways, it uses ACE2 receptors as the doors.

During the first months of the pandemic, Brevini and his 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 gate that the virus uses, is expressing itself in our cells,'” Brevini said. Additionally, the researchers had unintentionally increased the number of ACE2 receptors in some of their liver cells. Brevini said the next scientific hypothesis came logically to her and her team: “If we have a way to increase the amount of receptors present on the cell – so the cells’ susceptibility to the virus – maybe we can use the same mechanism. to reduce the amount of receiver.

She and her co-authors began to pull on this thread, testing UDCA on cultured clusters of cells from the gallbladder, lungs, and intestines and determining that it reduced levels of ACE2 in all three types of cells. Subsequent infection of these cell masses with SARS-CoV-2 significantly reduced the amount of viral genetic material compared to the clumps that had not received the drug. They repeated this experiment on mice and hamsters before moving on to a pair of human lungs on a mechanical ventilator. This part, Brevini said, was “like Frankenstein”.

“You see the lungs outside the body, and there’s a ventilator, and you see them inflating and deflating. I was blown away seeing this experience,” she 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 of 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 therapies require years of clinical studies before becoming a living human being, but UDCA is already widely prescribed to treat cholestatic liver disease. By comparing COVID-19 infection data from patients with chronic liver disease who did or did not take UDCA, Brevini and colleagues were able to analyze the results of a natural experiment. They found that patients with UDCA had a 46% reduced likelihood of contracting COVID-19; when they caught the virus, they were less likely to have moderate, severe or critical forms of the disease compared to patients with liver disease not taking the drug.

Finally, eight healthy volunteers agreed to take UDCA in pill form for five days. Researchers measured ACE2 levels in their noses with daily nasopharyngeal swabs, finding reduced levels of receptors even within days. Brevini said the discovery gave him hope that one day the pill could be used as a way to reduce the risk of getting an infection, with or without exposure.

“Let’s say you’re having lunch with your colleague one day and then the next day he’s texting like, ‘I’m so sorry, I’ve developed COVID,'” Brevini said. “If you have had your vaccine, you are protected from that point of view, but is there anything more you can do? We think you could take it preventively to reduce the chances of this particular virus infecting your cells. »

“It is remarkable that a drug that is safe and available” can 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 in a E-mail. “The drug certainly merits further testing” in a randomized, prospective human clinical trial, he added.

Even so, Lipton warned that UDCA can have unwanted side effects on blood pressure and kidney function in humans, which can occur when the number of ACE2 receptors on a cell is decreased.

“I am concerned that widespread use of the drug will reveal serious and undesirable side effects, especially in vulnerable older populations who would need drug treatment the most,” he said.

Other groups of researchers are working on ways to reduce ACE2 receptors only in cells vulnerable to SARS-CoV-2 infection, in the airways and lungs. Lipton conducted a study that was published in Nature Chemistry Biology in September and found that a targeted method of blocking ACE2 decreased the ability of the virus to infect human cells and hamsters.

What these methods have in common is a promising tactic for combating this virus that we’ve always had in our arsenal: slamming the doors of our cells and preventing infection in the first place.