Research exposes new vulnerability for SARS-CoV-2
Electrostatic interactions enhance the spike protein's bond to host cells


Date:
August 11, 2020
Source:
Northwestern University
Summary:
Using nanometer-level simulations, researchers have discovered
a positively charged site (known as the polybasic cleavage site)
located 10 nanometers from the actual binding site on the spike
protein. The positively charged site allows strong bonding between
the virus protein and the negatively charged human-cell receptors.



FULL STORY ========================================================================== Northwestern University researchers have uncovered a new vulnerability
in the novel coronavirus' infamous spike protein -- illuminating a
relatively simple, potential treatment pathway.


==========================================================================
The spike protein contains the virus' binding site, which adheres to
host cells and enables the virus to enter and infect the body. Using nanometer-level simulations, the researchers discovered a positively
charged site (known as the polybasic cleavage site) located 10 nanometers
from the actual binding site on the spike protein. The positively charged
site allows strong bonding between the virus protein and the negatively
charged human-cell receptors.

Leveraging this discovery, the researchers designed a negatively charged molecule to bind to the positively charged cleavage site. Blocking this
site inhibits the virus from bonding to the host cell.

"Our work indicates that blocking this cleavage site may act as a viable prophylactic treatment that decreases the virus' ability to infect
humans," said Northwestern's Monica Olvera de la Cruz, who led the
work. "Our results explain experimental studies showing that mutations
of the SARS-CoV-2 spike protein affected the virus transmissibility."
The research was published online last week in the journal ACS Nano.

Olvera de la Cruz is the Lawyer Taylor Professor of Materials Science and Engineering in Northwestern's McCormick School of Engineering. Baofu Qiao,
a research assistant professor in Olvera de la Cruz's research group,
is the paper's first author.

Made up of amino acids, SARS-CoV-2's polybasic cleavage sites have
remained elusive since the COVID-19 outbreak began. But previous research indicates that these mysterious sites are essential for virulence and transmission. Olvera de la Cruz and Qiao discovered that polybasic
cleavage site is located 10 nanometers from human cell receptors --
a finding that provided unexpected insight.

"We didn't expect to see electrostatic interactions at 10 nanometers,"
Qiao said. "In physiological conditions, all electrostatic interactions
no longer occur at distances longer than 1 nanometer." "The function
of the polybasic cleavage site has remained elusive," Olvera de la Cruz
said. "However, it appears to be cleaved by an enzyme (furin) that is
abundant in lungs, which suggests the cleavage site is crucial for virus
entry into human cells." With this new information, Olvera de la Cruz
and Qiao next plan to work with Northwestern chemists and pharmacologists
to design a new drug that could bind to the spike protein.

The research, "Enhanced binding of SARS-CoV-2 spike protein to receptor by distal polybasic cleavage sites," was supported by the U.S. Department
of Energy (award number DE-FG02-08ER46539), the Sherman Fairchild
Foundation and the Center for Computation and Theory of Soft Materials
at Northwestern University.


========================================================================== Story Source: Materials provided by Northwestern_University. Original
written by Amanda Morris. Note: Content may be edited for style and
length.


========================================================================== Journal Reference:
1. Baofu Qiao, Monica Olvera de la Cruz. Enhanced Binding of SARS-CoV-
2 Spike Protein to Receptor by Distal Polybasic Cleavage Sites. ACS
Nano, 2020; DOI: 10.1021/acsnano.0c04798 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/08/200811120227.htm

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