Consider the spike protein: The Covid-19 weak spot we can attack

Targeting the infamous spike protein could stop Covid-19 infections before they start.

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At this stage of the pandemic, the structure of SARS-CoV-2 — the virus that causes Covid-19 — is cemented in most of our brains. Picture a tiny sphere covered in scary-looking spikes.

These spike proteins, which stud the surface of the virus, are infamous for their ability to attach to human cell receptors called ACE2, enabling the virus to efficiently enter human cells and wreak havoc on the body.

But while spike proteins get a deservedly bad wrap, they also offer an opportunity to stop Covid-19 infections before they start.

Compared to fighting infection once the virus is already inside the body, preventing the spike protein-ACE2 interaction is a relatively simple, researchers say. Ultimately, it could be a more effective approach.

The process of how the virus goes from attaching to and entering a cell to becoming an infection that leads to you getting sick and contagious is "very complex," says Stephen Goldstein, an evolutionary virologist who studies coronaviruses at Utah University Health. He tells Inverse that the simplest way, in theory, to interrupt that process is to prevent the virus from attaching or entering in the first place.

"By targeting the spike protein, you can hopefully interfere with that first step, which, although not terribly simple, has the potential to be much simpler than going after all the complicated processes that occur subsequent to the virus getting into a cell," Goldstein explains.

Goldstein compares this approach to fighting off a home invader.

"If somebody shows up to rob your house, the simplest way to prevent that is to have your door locked, right?" Goldstein says. "If your door is open, and then they get in, then maybe you have to chase them through the house to stop them from what they're doing. If you just lock your door, they can't even get in."

Scientists are still honing the best way to run interference between spike proteins and ACE2 receptors, the major areas by which the virus sneaks in and infects human cells. But new research, on monoclonal antibodies, convalescent plasma, and polybasic cleavage sites suggests we are getting closer to leveraging spike proteins to our advantage.

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An illustration of the novel coronavirus' spike protein structure.

Radoslav Zilinsky

What is the coronavirus spike protein?

While an outbreak of the scale and scope of the Covid-19 pandemic had been predicted for years, experts still weren't intimately familiar with the specific behavior and structural dynamics of SARS-CoV-2 when it emerged.

Faced with this previously unknown virus circulating through the global population at lightning speed, scientists raced to sequence its viral structure. Thanks to structural similarities to its cousin virus, SARS-CoV, researchers pinned down the mechanics of the novel coronavirus relatively quickly.

They honed in on the spike protein as a crucial target for diagnosis and therapeutics. That's because the spike protein, or S protein, facilitates viral entry into host cells.

"Past research on SARS[-CoV] allowed us to understand how this virus is infecting cells almost immediately," Goldstein says. He notes there is still a lot we don't know about the Covid-19 virus, but these structural fundamentals jumpstarted scientists' understanding of how the virus behaves.

"It was clear very quickly, based on the similarity between the sequence of this spike protein and the spike protein of the original SARS virus, that this virus probably used ACE2 as a receptor," Goldstein explains.

This is a 3D atomic scale map, or molecular structure, of the 2019-nCoV spike protein. The protein takes on two different shapes, called conformations—one before it infects a host cell, and another after infection. This structure represents the protein before it infects a cell, called the prefusion conformation.


After the spike protein attaches to the ACE2 receptor, the viral and the human cell membranes fuse. This fusion creates an opening for the virus to invade human cells and start infecting a person's body.

Once the viral genome is inside, a complex, rapid process of viral replication kicks off. In turn, the immune system is triggered into action, producing antibodies and immune cells to fight the infection.

According to scientists, if we can take down viral intruders before getting in the door, we can stop Covid-19 infections before they start. And we can more effectively contain the pandemic.

How to stop an infection before it starts — In a new study, scientists inched closer to creating a therapy that acts as a Covid-19 bouncer. This research was published August 2 in the journal ACS Nano.

After analyzing the cellular and molecular dynamics of the virus, researchers pinpointed a weak spot of the viral structure — just 10 nanometers away from the binding site of the spike protein. This tiny but pivotal location is positively charged, which allows strong bonding between the virus protein and negatively charged human cell receptors.

The study team subsequently designed a negatively charged molecule to bind to the positively charged location, also known as a cleavage site. Blocking this site inhibited the virus from bonding to the host cell.

Study co-author Monica Olvera de la Cruz, a researcher at Northwestern McCormick's school of engineering, tells Inverse that the blockage of this cleavage site could work as a viable prophylactic treatment that decreases the virus’s ability to infect humans.

"It would be a very easy, targeted site if you want to block it," Olvera de la Cruz says.

She also cautions that we're still many studies away from developing a treatment that takes this therapy from theory to practical use.

"We're looking at something that is possible to be adopted," Olvera de la Cruz explains. "Nevertheless, there is still a long way to prove it."

Commenting on this new research, Goldstein agrees that one "could think of the spike ACE2 interaction as a weak spot."

It is conceptually pretty simple regarding how you would prevent infection by targeting this interaction, he reasons — "but I don't think this group found it."

Is there a link between spike proteins and coronavirus mutations?

Recent reports describe a highly infectious strain of the coronavirus called D614G that is sweeping the world.

Olvera de la Cruz says her team's results help "explain experimental studies showing that mutations of the SARS-CoV-2 spike protein affected the virus transmissibility.”

Goldstein acknowledges that there is "some evidence" that this new variant of Covid-19, D614G, may affect the ability of the virus to infect cells and how efficiently this process occurs. But it's too early to say for sure.

"We don't have clear evidence yet that it is more transmissible," Goldstein says. "There's certainly no evidence that it's more lethal." But regardless of how interesting it is that mutations may be at play, Goldenstein notes that mutation-or-not, the possibility doesn't change "what needs to be done to contain the outbreak."

"People's behaviors and how they go about their lives, and how they think about the road through this should not change at all based on what they may read about these interesting scientific questions with respect to mutations in the spike protein," he argues.

The spike protein mutations that would be "immediately concerning," Goldstein says, are those that would render monoclonal antibodies or vaccines ineffective. But there's no evidence for any mutations causing this undesirable outcome.

Future spike-protein linked therapies — The spike protein continues to be a crucial target of attack. Still, the best route of attack is uncertain.

In labs around the world, scientists like Olvera de la Cruz are also aiming to neutralize the spike protein-ACE2. Most often, approaches are via:

Both of these potential therapies, which haven't completed trials showing they are safe or effective on a large scale, influence the spike protein-ACE2 interaction. The better we come to understand the spike protein and its ability to infect, the closer we'll be to an effective treatment for Covid-19.

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