All it takes is a simple cough: a sharp intake of breath, the compression of air in the lungs, and the throat flying open to spew air, spit, and mucus. If the person coughing is infected with the novel coronavirus, it comes along for the ride on droplets, which can travel up to 50 miles per hour. When someone breathes those droplets in, the virus can get into the lungs. Once inside, it uses a spike protein on its surface to target an enzyme—ACE2—scattered over the outsides of the airway’s cells. If the spike protein connects with its target, the coronavirus uses ACE2 as a door to slip inside the cell. Thus begins an infection.
ACE2, the enzyme that the novel coronavirus uses to enter cells, helps regulate blood pressure in our bodies. Early in the pandemic, scientists thought that certain blood pressure drugs, taken by millions of people, increased ACE2 levels, in turn raising the risk of contracting COVID-19. But as more research emerges, this idea has been flipped on its head: scientists now wonder if these blood pressure medicines, known as ACE inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs), might help fight COVID-19. We review the existing drugs in clinical trials to test that theory and the companies developing novel treatments that target the ACE2 system.
During the early days of the coronavirus outbreak, researchers hypothesized that the likelihood of contracting COVID-19, the disease caused by the novel coronavirus, could be related to the amount of ACE2 on someone’s cells—the more doors for the virus to enter through, the higher the risk.
That idea prompted doctors around the world in March to warn the millions of people taking two classes of blood pressure medications, angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs), of a potential danger: these medications appear to increase ACE2 levels in cells, at least in some studies, so the drugs may make their users more susceptible to the novel coronavirus, SARS-CoV-2.
But ACE2 doesn’t make such a tidy villain in this story. As the pandemic has raged on, some scientists have begun to think those same blood pressure medicines may be a good treatment for COVID-19.
The medications don’t directly affect ACE2. But they do affect the renin-angiotensin system, which regulates blood pressure, the circulatory system, and other functions in the body. ACE2 is a critical component in this system because it regulates a hormone called angiotensin II. Evidence is gathering that if angiotensin II isn’t kept in check, it may play a role in the severe lung damage and runaway inflammation in COVID-19 patients, which can lead to death.
Scientists are trying to figure out ACE2’s complicated role in the disease. Since January, over 700 studies on the relationship between ACE2 and COVID-19 have been published, according to CAS, a division of the American Chemical Society, which publishes C&EN.
Researchers are also actively working on ways to better control angiotensin II in our bodies by testing older drugs and developing new ones. Widely prescribed blood pressure drugs, such as captopril, lisinopril, and losartan, either stop production of angiotensin II, or make the hormone ineffective, and clinical trials to test their use in treating COVID-19 are either starting up or underway. Scientists are also working on therapies that can directly lower levels of ACE2. The results from these trials may teach us more about the link between SARS-CoV-2 and ACE2, and help identify a way to control and treat the disease caused by this coronavirus.
A DOOR FOR SARS-COV-2
Early on in the pandemic, researchers were confident that the SARS-CoV-2 spike protein was sticking to ACE2—it’s the same doorway used by the coronavirus that caused an earlier outbreak of severe acute respiratory syndrome (SARS). By early March, scientists had captured a snapshot of the virus bound to ACE2, confirming their suspicions.
But even before they’d verified that ACE2 was the viral gateway to human cells, researchers were wondering about the connection between the enzyme and blood pressure, or antihypertensive, drugs. As early as December 2019, Chinese doctors noticed a pattern emerging: COVID-19 seemed to be worse for the elderly and for people with certain chronic conditions. “The risk factors appeared to be hypertension, heart disease, or other cardiovascular disease,” says Paul Insel, a pharmacologist at the University of California, San Diego (UCSD). All those conditions are often treated with drugs such as ACEIs and ARBs that regulate the renin-angiotensin system in the human body. ACE2 plays an important role in that system and can be found all over the body: in the lungs, heart, kidneys, and, as scientists are finding out, inside the nose and the gastrointestinal tract.