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.
It’s a yin and yang between how much angiotensin II is made, and how much is broken down.
Matthew Sparks, nephrologist and assistant professor of medicine at Duke University
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 coronaviruses that caused earlier outbreaks of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). 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.
As worries deepened in early 2020 about blood pressure drugs increasing people’s susceptibility to SARS-CoV-2, scientists from Switzerland, Greece, Australia, and the US published letters in multiple journals, warning of the potential danger. News stories amplified their fears, and some people with high blood pressure and diabetes began to wonder if they should stop taking these drugs.
But going off these medicines altogether creates a different problem. John Chorba, a cardiologist and assistant professor at the University of California, San Francisco (UCSF), says that it’s hard to know whether the potentially higher risk of COVID-19 outweighs the risk that chronic conditions could worsen if people stop their antihypertensive medications. “A lot of these medicines are very protective for people with heart disease” and related illnesses, he says. At least 14 health societies and associations, including the American Heart Association, the American College of Physicians, and the International Society of Hypertension, have released statements saying that people on antihypertensive drugs should continue taking these medications.
Franz Messerli, a cardiologist at Swiss Cardiovascular Center in Switzerland, says it’s understandable that patients are scared their drugs might make them more susceptible to COVID-19. However, “nobody has shown that this is indeed the case,” he says. It’s a complex and multistep process to go from upregulation of ACE2 to the SARS-CoV-2 virus entering the cell, he points out.
Scientists aren’t even sure that these blood pressure medicines do raise ACE2 levels in humans. So far, the evidence is scant. Several papers show increases in ACE2, but many of them are based on studies in animals, says Matthew Sparks, a nephrologist and assistant professor of medicine at Duke University. In these studies, scientists gave rats blood pressure medications for a few days or weeks, and then measured the rats’ ACE2 levels in different organs. While some found an increase in the enzyme that correlates with taking the drugs, similar studies show the opposite effect, Sparks says.
Moreover, scientists gave the animals in those studies very high doses of the drugs, making the results a poor model for what’s happening with humans, says Krishna Sriram, a postdoctoral researcher in Insel’s lab at UCSD. Some human studies have been conducted, but Sparks explains that ACE2 levels are more challenging to detect in people because doctors can only measure how much ACE2 is in the blood. That may not reflect what’s happening in organs such as the lungs, which are one of the places scientists think the virus is getting into the body.
“It’s possible that people were trying to connect some dots that shouldn’t have been connected, basically,” Insel says. “But it was a natural question to ask.”
While studies have not unequivocally disproven the idea that taking blood pressure medicine can increase the severity or infection rates of COVID-19, many scientists have moved beyond this hypothesis. Instead, they’re shifting their thinking in the opposite direction: “It may even be beneficial if you’re on these drugs,” Insel says.
Striking a balance
The question of whether these blood pressure drugs help or harm patients with COVID-19 is critical, due to the drugs’ widespread use, doctors say. Worldwide in 2017, over 40 million people took ACEIs, and over 80 million took ARBs. Both types of drug lower blood pressure by rebalancing the renin-angiotensin system.
This system works by keeping the blood pumping through our bodies at the right pressure. And it does so by holding its star player, an 8-amino-acid peptide called angiotensin II, in check.
For instance, we need more angiotensin II if our blood pressure gets too low or if we become dehydrated. The molecule also controls some immune responses in our bodies, such as wound healing and inflammation, which is helpful when we’re injured. If angiotensin II levels get too high, however, the hormone can cause fibrous tissue to build up in our hearts, kidneys, and lungs, impairing the organs’ abilities to work properly.
Working together with the related enzyme ACE1 and the peptide angiotensin I, ACE2 helps maintain proper levels of angiotensin II. If our bodies need angiotensin II levels to rise, ACE1 pulls two amino acids off of angiotensin I to turn it into angiotensin II. ACE2 comes into play when our body needs to cut down levels of angiotensin II. The enzyme snips off one more amino acid to create angiotensin 1-7, an anti-inflammatory peptide.
“It’s a yin and yang between how much angiotensin II is made and how much is broken down,” Sparks says.
Cooperation and control
Blood pressure is regulated by the renin-angiotensin system, which relies on several players to maintain the right levels of a hormone called angiotensin II. To enter our cells, the novel coronavirus binds to one of those players, ACE2, preventing it from breaking down angiotensin II into angiotensin 1-7. Scientists think this may cause hormone levels to soar out of control, potentially contributing to the lung inflammation that makes COVID-19 so deadly. In molecular models: C is gray, H is white, N is blue, O is red.
Scientists are beginning to suspect that an imbalance in the amount of angiotensin II in our bodies could be what’s driving the severe lung and heart damage seen in some COVID-19 patients. Sriram explains that to breathe, our lungs rely on “critical little compartments” called alveoli, which are lined with cells coated in ACE2. When SARS-CoV-2 grabs ACE2, it could prevent the enzyme from breaking down angiotensin II, and levels of the hormone might then skyrocket. The increase in angiotensin II levels may in turn cause lung cells to die, which may prompt the cells to release cytokines, small proteins that drive inflammation.
This could create a feedback loop: more inflammation may cause more cell death, which might cause lung cells to release more cytokines. “The stronger the effect of silencing ACE2 in the cells, the more rapidly you’re going to have cell death within these alveoli,” Sriram says.
It feels all high risk, right? Because if you get it wrong, it could actually make a big difference in a very short period of time.
John Chorba, cardiologist and assistant professor at the University of California, San Francisco
But then it could get even worse: the death of the alveoli could cause surrounding cells called fibroblasts to start secreting a collagen matrix, causing scar tissue to form in the lungs. The alveoli would fill with fluid, making patients more susceptible to pneumonia. “The initial event that drove [lung] injury was the SARS-CoV-2 infection,” Sriram says. But what’s actually killing patients is pneumonia, he says.
Sparks stresses that this is all still a hypothesis—researchers have yet to find solid evidence of this feedback loop in COVID-19 patients—but says the results of human studies are starting to trickle in.
From harmful to helpful
Given the limited, but growing, clinical evidence that angiotensin II levels could be driving lung damage in COVID-19 patients, scientists are starting to wonder whether blood pressure medicines—the same ones that some doctors worried about 2 months ago—might actually make good treatments for the disease because they keep angiotensin II regulated. ARBs stop angiotensin II from binding to its receptor, rendering the hormone useless. ACEIs, or ACE inhibitors, prevent ACE1 from cleaving angiotensin I to form angiotensin II. While the drugs don’t directly affect ACE2, they could help mitigate the effect of SARS-CoV-2 hijacking ACE2 and preventing the enzyme from breaking down angiotensin II.
Clues are emerging that these blood pressure drugs might be protective against COVID-19. In a 2005 study, mice infected with the related SARS coronavirus had lower ACE2 levels and excess angiotensin II. When researchers gave the mice losartan, an ARB, the mice had less lung damage, Sparks says. He also points to evidence that angiotensin II triggers lung injury in viral infections such as influenza and respiratory syncytial virus (RSV).
Rise in research
Journal publications on ACE2 and COVID-19 have surged since January 2020.
Other studies show that people with viral pneumonia who take blood pressure medications fare slightly better than people who don’t, Swiss Cardiovascular Center’s Messerli says. “This could indicate that the drugs confer some cardiopulmonary protection,” he says.
But experts stress that evidence from animal models and other diseases is not enough. “Really, what we need is high-quality data,” Sparks says. “And those are going to come from clinical trials that are currently ongoing.” Many of these, he says, are examining patients who come to the hospital with COVID-19 and are already taking blood pressure medications. The patients are randomly assigned to one of two groups: half stop taking their medications, and half continue. Other clinical trials are testing whether COVID-19 patients who don’t normally take blood pressure drugs will recover faster if given the medicine.
Researchers are also trying to understand if the two classes of drugs, ACEIs and ARBs have the same effect on SARS-CoV-2, or if one might work better than the other. “I think they both should be studied separately and not lumped together,” Sparks says.
More than 30 clinical trials have launched to study the effect of blood pressure medications on people with COVID-19. The majority of these trials involve losartan, the ninth most prescribed drug in the world. It’s a generic pill that over 50 million people took in 2017, and it’s one of the World Health Organization Model List of Essential Medicines.
Meanwhile, some groups are focusing on treatments that directly target ACE2. Apeiron Biologics, an Austrian biotech company, has created a recombinant form of ACE2 that acts as a decoy to trick SARS-CoV-2 into binding it instead of its counterparts on cells. A Phase II trial of the medication, called APN01, will begin soon and will enroll 200 patients, who will either get an intravenous dose of the drug twice a day or a placebo. Similarly, Vir Biotechnology and Alnylam Pharmaceuticals are planning a study that will use RNA interference, which can selectively shut down protein translation, to prevent cells from making ACE2 and TMPRSS2, another protein needed for viral entry into cells.
Right now, it’s just a waiting game. Many of these clinical trials are months away from yielding data that could answer the question of whether these drugs help or harm COVID-19 patients. “It feels all high risk, right? Because if you get it wrong, it could actually make a big difference in a very short period of time,” UCSF’s Chorba says. This is a common problem in medicine, but the world is really seeing it right now, he says. “Sometimes you need to make a decision based on not really knowing all the information.”
A great many people are on medications that disturb the renin-angiotensin system, Sparks says. “We need to know the answer to this question. Because a lot of lives are at stake here,” he says. “But right now, there’s just not enough information.”