The coronavirus sneaks into cells through a key receptor. Could targeting it lead to a treatment?

Nearly 20 years ago, when a different coronavirus struck, Michael Farzan and his team figured out how it was getting into human cells: targeting a specific receptor called ACE2 found on certain cells.

During this year’s ongoing novel coronavirus outbreak, that receptor has attracted fresh attention as a potential target for drug companies because it seems to offer a cellular doorknob for this coronavirus, too.

Farzan, a virologist at the Scripps Research Institute’s Florida campus, and other experts believe treatments targeting ACE2, or angiotensin converting enzyme-2, could be the key to unlocking either a coronavirus vaccine or a treatment for Covid-19. The work targeting the receptor is one pathway among dozens that biotech and pharmaceutical companies are exploring as they race to find drugs that could help bring the pandemic under control.

Three pharmaceutical companies are working on two ACE2-related drugs — each working with the receptor in diametrically opposite ways. Apeiron Biologics, a company based in Austria, is trying to offer the virus more ACE2 to bind with, in hopes that the flood will confuse the virus. Alnylam Pharmaceuticals and Vir Biotechnology are trying to offer it less, thinking it will struggle to take hold in the body with less to bind to.

Apeiron expects to have results from its latest clinical trial in late fall. Alnylam’s ACE2 program is much further from reality; the company doesn’t expect to have something it could test in humans for several more months.

In a healthy person, the ACE2 receptor chops up two forms of a protein called angiotensin to keep blood pressure stable, among other things. SARS and the novel coronavirus, however, use the receptor to infiltrate cells, according to a paper published in March in Cell. The virus can latch onto ACE2 and sneak inside, replicating itself inside the cell and then wreaking havoc throughout the body.

Normally, ACE2 is found on lung, kidney, heart, and gut cells. But scientists recently found ACE2 receptors on the cells in peoples’ noses — an “aha” moment for people like Farzen who had studied the 2003-era SARS virus.

“It was never quite clear how the virus trafficked all the way to the lower respiratory tract to give you this horrendous pneumonia,” he said.

Understanding how the new coronavirus exploits ACE2 is powerful information — but scientists haven’t agreed on what it ultimately means. As recently as March, more ACE2 was thought to be a risk factor for people with Covid-19. The French health ministry even warned against prescribing non-steroidal anti-inflammatories like ibuprofen because those drugs are thought to increase the number of ACE2 receptors on cells.

However, the World Health Organization and the European Medicines Agency both declined to make similar warnings, citing a lack of evidence. And some scientists and pharmaceutical companies suspect that adding more ACE2 into the body might actually distract the virus and help patients.

They hope that using a floating version of enzyme, rather than the ones that stick onto cells, could trick many of the viruses inside a person’s body. If the virus binds with the drug rather than onto the cells, it can’t replicate and spread.

“As I like to say, ‘It’s the virus, stupid.’ Stop the virus to stop the disease,” said Farzan, who is not involved with Apeiron, Alnylam, or Vir.

Apeiron first started developing its experimental treatment targeting ACE2 in the mid-2000s, after the first SARS outbreak. In 2010, it licensed the drug to GSK for about $17 million.

The larger pharmaceutical company put it into clinical trials for acute respiratory distress syndrome and acute lung injury, but decided to cut the program in the middle of last year, along with 10 other programs focused on respiratory illnesses. Apeiron got the rights to the drug back.

“We were sitting there thinking, ‘OK, what should we do with this?’ And all of a sudden this virus started,” said Apeiron’s CEO, Peter Llewellyn-Davies.

Because GSK had already run clinical trials in humans to show that the drug was safe, Apeiron was quickly able to set up another trial at 11 sites across Europe. The company hopes to recruit about 200 patients, who will receive two treatments per day over the course of a week.

Apeiron is trying to prepare for the best-case scenario: that its drug will actually work for people with Covid-19. The company has asked its manufacturer to make enough to get it through the current trial; over the next few weeks, Llewellyn-Davies said, it will be analyzing how much demand it might need to anticipate in the event the trial results are good.

But Apeiron probably won’t be able to bring the drug to the market on its own.

“We will probably need a pharmaceutical partner to do this,” Llewellyn-Davies acknowledged. “It’s certainly worth going into negotiations as soon as possible because, you know, things might happen very, very quickly.”

Alnylam and Vir are taking an entirely different approach. Alnylam’s products rely on a technique known as RNA interference, through which scientists use strands of genetic material to mute disease-causing genes.

Normally, they’re silencing a protein that’s causing a disease because there’s too much of it in the body or it’s mutated. In this case, though, they’re hoping to use the technique to silence the ACE2 receptor. Without the receptor to bind to, Alnylam believes, the virus won’t be able to get in.

This “host factor” approach is more roundabout than a typical drug. Technically, Alnylam and Vir’s treatment won’t do anything to the virus itself. It will still enter the body if people come into contact with it, but it won’t have nearly as many opportunities to invade people’s cells. If it can’t get into people’s cells, it can’t survive and spread.

“There are other antivirals that act on host factors,” Alnylam CEO John Maraganore noted, citing interferon, a synthetic version of a protein that has become a treatment for hepatitis C and multiple sclerosis. “In the history of developing antivirals, [targeting] host factors are an established strategy.”

But as Maraganore noted, there are big questions about whether knocking down ACE2, even temporarily, could have unintended consequences. Angiotensin levels can regulate a person’s blood pressure and start (or stop) inflammatory processes.

“It’s very, very complicated. And I have to say that humanity does not have a clear understanding of [ACE2’s] role,” Farzen said.

Even if the drug is safe, getting it where it needs to be in order to have an effect could be another challenge.

Delivering RNA-based drugs anywhere other than the liver has been a perennial challenge, noted Jim McSwiggen, a biotech consultant who has worked for several RNA companies — and who was one of three co-inventors on a patent filed in the early 2000s on a way of using RNA interference to treat SARS.

In this case, McSwiggen said, there might be a way to put strands of RNA into bubbles of fat. Patients could potentially inhale them as a dry powder.

“I don’t know how small the particles would have to be to get into the deepest part of the lungs,” he said. “But there’s a lot of people who think about drug delivery to the lung. So I’m sure that there are people who can come up, solve that problem.”

Alnylam thinks it has a solution to that problem; it has already run some animal studies on a way to get its drugs into the lungs for other indications.

But Farzen said he was skeptical that Alnylam and Vir’s approach is the right one — certainly at first. “They have a hammer, and they tried to find a nail. But the nail is not a good nail here,” he said.

Maraganore noted that the ACE2 program is just one of the Covid-19 programs Alnylam and Vir are working on; one of their other efforts would use RNA interference to attack the virus directly.

And Maraganore also said he hoped that all the attention now being paid to ACE2 and other antiviral programs would continue even after the worst of the pandemic has passed.

“We have a lot of societal ADD when it comes to the work that we do on antivirals,” he said. “We have a tendency as a society to, you know, launch these big efforts around the time of a public health crisis.

“When the public health crisis goes away, you know, we all sort of downplay it and don’t do work on it and ignore it or put it aside,” Maraganore said. “And sometimes, you have to get hit by a two-by-four like this current pandemic to realize that that’s a really bad idea.”