A new understanding of the neuropilin-1 protein may speed up COVID vaccine research

In this image, the box represents a human call and the green object is SARS-CoV-2. The spike protein of COVID-19 virus attaches to the ACE2 protein receptor (pink) and infects human cells. Credits: University of Bristol, CC BY-ND

When it comes to how the coronavirus invades cells, it takes three times to tango. The dance began with the ACE2 receptor, a protein on human cells that allows SARS-CoV-2, the virus that causes COVID-19, to invade and infect cells. But now we are entering a new dance partner (another protein) that exists in human cells. The tango of these three proteins (two humans and one virus) increases the ability of SARS-CoV-2 to enter human cells and replicate to cause disease.

COVID-19 has crippled healthcare systems and economies around the world.Extraordinary efforts are underway to develop vaccines and other therapies to counter this. Virus.. However, for the success of these efforts, it is important to understand how the virus invades cells. for that reason, In two papers Published in Science, Two teams independent protein What is called the neuropilin-1 receptor is an alternative gateway for SARS-CoV-2 to invade and infect. Human cells.. This is a big step forward and a surprise, as scientists believed that neuropilin-1 played a role in helping neurons connect properly and helping blood vessels grow. Prior to this new study, no one suspected that neuropilin-1 would be the door for SARS-CoV-2 to enter the nervous system.

With my colleague I I was particularly intrigued by these reports because of how I study as a neuroscientist. Pain signal It was triggered and transmitted to the brain, and the activity of neuropilin-1 was also investigated. In a recent paper, our team is on how Neuropilin-1 Involved in pain When a signal and the SARS-CoV-2 virus attach to it, it blocks the transmission of pain and is a way to relieve pain. New studies show that neuropilin-1 is an independent gateway for the COVID-19 virus to infect cells. This finding provides insights that may reveal ways to block the virus.

Neuropilin-1 helps SARS-CoV-2 enter

A protein called spikes on the outer surface of SARS-CoV-2 allows the virus to attach to protein receptors in human cells.Recognize that small fragments of spikes resemble regions of known human protein sequences Binds to neuropilin receptors, Both research teams have realized that neuropilin-1 may be important for cell infection.

Using a technique called X-ray crystallographyThis allows researchers to see the three-dimensional structure of spiked proteins, and other biochemical approaches, at the resolution of individual atoms. James L. Daly and colleagues at the University of Bristol This short sequence from spikes attached to neuropyrin-1 is shown.

In laboratory experiments, the SARS-CoV-2 virus was able to infect fewer human cells lacking neuropyrin-1.

In cells containing both the ACE2 protein and the neuropilin 1 protein, SARS-CoV-2 infection was greater than in cells containing only one of the “doorways”.

Daly et al. Showed that SARS-CoV-2 used fewer cells to infect. A small molecule called EG00229 Alternatively, an antibody that blocks access to the spike protein neuropilin-1.

Neuropilin-1 receptors help the virus infect cells

Using a similar method, German and Finnish researchers I came to the same conclusion as the first study. Specifically, the team showed that neuropilin-1 is important for the SARS-CoV-2 virus to invade and infect cells.

By using antibodies to block one region of the neuropilin-1 receptor protein, researchers have shown that SARS-CoV-2 from patients with COVID-19 cannot infect cells.

In another experiment Ludovico Cantuti-Castelvetri and colleagues at Technische Universität München We attached silver particles to a synthetic spike protein made in the laboratory and discovered that these particles could enter cells that carry neuropyrin-1 to the surface. When they did the same experiment with live mice, they found that silver particles entered the cells that line the inside of the nose. Researchers were surprised to discover that spike proteins can also enter neurons and blood vessels in the brain.

Using tissue from human autopsy, Cantuti-Castelvetri and colleagues We noted that neuropilin-1 is present in the cells that line the human respiratory and nasal cavities, but not the ACE2 protein. This indicates that neuropilin-1 provides an independent gateway for the COVID-19 virus to infect cells.

In addition, the cells lining the nasal cavity from patients with COVID-19 who were positive for neuropilin-1 were also positive for spike proteins. These findings confirmed that spikes use the neuropilin-1 protein to infect human cells in areas of the body where ACE2 is absent.

Neuropilin-1 can block viruses, cancer and pain

With a surprising discovery recently reported Our lab, SARS-CoV-2 spike protein has a pain-relieving effect.. Even more surprising was the discovery that this analgesia was associated with the neuropilin 1 receptor.

We have demonstrated that spikes prevent proteins from binding to neuropilin-1, block pain signals, and relieve pain. This is because many people produce this protein, called vascular endothelial growth factor A (VEGF-A). cell In the body — under normal circumstances, it binds to neuropilin-1 and initiates the process of pain signaling by stimulating neurons that convey pain messages.

Therefore, the virus has revealed a potential new target for managing chronic pain, the neuropilin-1 receptor. Once we can decipher how neuropyrin-1 contributes to pain signaling, we can design ways to target it and block pain.

Our lab takes advantage of how spikes interact with neuropyrin-1 to design new pain suppressants. In this report On the preprint server BioRxiv, we identified a series of novel compounds that bind to neuropilin-1 in a way that mimics spikes. These molecules can interfere with the function of neuropilin-1, including the invasion of the SARS-CoV-2 virus, and can block pain signals and even the growth of cancer.

More dance partners to come

Studies by Daly and his colleagues, and Cantuti-Castelvetri and his colleagues, have shifted our collective focus to neuropilin-1 as a potential new target for COVID-19 therapy.

These studies also influence the development of vaccines against spike proteins. Perhaps most importantly, the neuropilin-1 binding region of the spike should be targeted for COVID-19 prophylaxis. Neuropyrin-1 is an indiscriminate mediator of viral invasion, as many other human viruses, including highly virulent strains of Ebola, HIV-1, and avian influenza, also share a characteristic sequence of this spike. It may be.

However, it seems that the tango is not over yet. More dance partners are emerging. PIKFyve kinase And CD147 – Two proteins – have also been shown to bind spikes and promote viral invasion. It is not yet known if these new partners will be the central stage or will play the second fiddle of ACE2 and Neuropilin 1.

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