Two Research Groups Discover Neuropilin-1 Aids SARS-CoV-2 Infection

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Two international teams—one led by UK-based researchers and the other by Finland and Germany-based scientists—have simultaneously uncovered that the neuropilin-1 protein helps the SARS-CoV-2 virus infect human cells.

The SARS-CoV-2 virus is already known to attach to the ACE2 protein found on the surface of various cells around the body, but the discovery that it also binds to neuropilin-1 may help explain why it is so transmissible compared with other coronaviruses and why it affects so many cells around the body. It might also explain some of the unusual symptoms such as loss of smell, as neurolipin-1 is expressed in neurons involved in smell in the nose.

“If you think of ACE2 as a door lock to enter the cell, then neuropilin-1 could be a factor that directs the virus to the door. ACE2 is expressed at very low levels in most cells. Thus, it is not easy for the virus to find doors to enter. Other factors such as neuropilin-1 might help the virus finding its door,” says Giuseppe Balistreri, Ph.D., a senior virologist at the University of Helsinki and co-corresponding author on one of the two papers published in Science.

Neuropilin-1 is one of two similar proteins that regulate blood vessel and nerve formation. It is expressed at higher than normal levels in some cancers and so has already been investigated as a potential target for cancer therapies. Both teams also tested whether inhibiting neuropilin-1 with specific antibodies could impact spread of the virus and indeed confirmed this in cell lines in the lab.

The SARS-CoV-2 virus infects human cells via its ‘spike’ protein. Once it has entered the cells it can then replicate and infect other cells around the body. Both teams working on this research discovered a link between the spike protein of the virus and neuropilin-1. The UK-based team used X-ray crystallography and biochemical approach to discover the role of neuropilin-1, whereas the other group produced lentiviral particles that were pseudotyped with the SARS-CoV-2 spike protein to investigate how the virus interacts with human cells.

The UK research, also published in Science, was led by the University of Bristol’s Peter Cullen, Ph.D., a professor of biochemistry; Yohei Yamauchi, M.D., Ph.D., a senior virologist from the School of Cellular and Molecular Medicine, and Boris Simonetti, Ph.D, a researcher working with Cullen.

“In looking at the sequence of the SARS-CoV-2 spike protein we were struck by the presence of a small sequence of amino acids that appeared to mimic a protein sequence found in human proteins which interact with neuropilin-1. This led us to propose a simple hypothesis: could the Spike protein of SARS-CoV-2 associate with neuropilin-1 to aid viral infection of human cells?” explain Cullen, Yamauchi and Simonetti.

“Importantly, by using monoclonal antibodies – lab-created proteins that resemble naturally occurring antibodies – or a selective drug that blocks the interaction we have been able to reduce SARS-CoV-2’s ability to infect human cells.”

Although both groups managed to block activity of the virus by blocking its interaction with neuropilin-1 in cells grown in the lab, it is unclear if blocking this interaction would have a beneficial effect on patients with COVID-19.

“It is currently too early to speculate whether directly blocking neuropilin could be a viable therapeutic approach, as this could lead to side effects. This will have to be looked at in future studies,” says Balistreri.

“Currently our laboratory is testing the effect of new molecules that we have specifically designed to interrupt the connection between the virus and neuropilin. Preliminary results are very promising and we hope to obtain validations in vivo in the near future,” he concludes.

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