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Scientists Have Found COVID-19's Inside Man, And They Know How To Shut Him Up

We've got your number, GRP78.


Dr. Katie Spalding

Katie has a PhD in maths, specializing in the intersection of dynamical systems and number theory.

Freelance Writer

SARS-CoV-2 viruses binding to ACE-2 receptors on a human cell, the initial stage of COVID-19 infection, conceptual 3D illustration
We've been thinking these guys were smart. They just had an inside man. Image credit: Kateryna Kon/

COVID-19 is a tricksy beast. As soon as you think you’ve got a handle on it, up pops some new variant, or a previously unheard-of long-term consequence of infection – and with a few noteworthy exceptions, all we’ve been doing for the last couple years is trying to keep up.

But sometimes, the gods of science will throw you a win. A new study, aimed at identifying a more reliable way to combat COVID-19 in the face of virus mutations and unvaccinated patients, has found that a certain protein, known as GRP78, may hold the key to controlling the virus’s replication rates.


“We now have direct evidence,” said research lead Amy S. Lee, a professor of biochemistry and molecular medicine at the Keck School of Medicine of the University of Southern California, in a statement. “GRP78 is a proviral protein that is essential for the virus to replicate.”

We already knew that GRP78 was implicated in the spread of COVID-19: it’s what’s known as a “chaperone protein”, and previous studies have shown it actually helps SARS-CoV-2, the virus that causes COVID-19, to invade and infect host cells. If you think of SARS-CoV-2’s infamous spike protein as the “key” which opens host cells’ ACE2 protein “locks”, then GRP78 is basically the guy pointing at the door and yelling, “Over here! This is the one you can get into!”

So the team decided to try to shut this guy up. They used two different techniques designed to inhibit or suppress the GRP78 protein – one, tested on cell cultures of human lung epithelial cells, used a special messenger RNA tool to suppress its production, while the other was a small molecule drug named HA15, recently developed as an anti-cancer drug.

“Lo and behold, we found that this drug was very effective in reducing the number and size of SARS-CoV-2 plaques produced in the infected cells, in safe doses which had no harmful effect on normal cells,” explained Lee.


Specifically, HA15 works by inhibiting GRP78 – which hints at another tantalizing consequence of the study. It turns out GRP78 has a hand in more than just COVID-19 replication: it seems to be the protein that makes cancers more deadly, and it’s been implicated in other serious viruses such as Ebola and Zika. This study, then, doesn’t just provide a new potential therapy against severe COVID-19 – it’s potentially a whole new way of fighting a plethora of diseases.

For now, though – particularly as case numbers continue to surge and new variants of the virus seem unstoppable – it’s the use against COVID-19 which is likely to make the headlines. With this new study, the team has shown that therapies targeting GRP78 could be more effective at protecting and treating people who contract COVID-19 than vaccines alone – particularly good news for those who can’t get vaccinated, but also important given the virus’s bananas ability to adapt and evade vaccine responses. 

“A major problem in fighting SARS-CoV-2 is that it is constantly mutating and adapting itself to more efficiently infect and multiply in its host cells,” said Lee. “If we keep chasing the virus around, this could become quite challenging and unpredictable.”

With the GRP78 protein, though, the team may have uncovered a secret weapon. Lock it up; stop it fraternizing with the enemy – and we might just get the advantage on the molecular stage.


The study is published in Nature Communications.


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