How to prevent the new coronavirus from entering the host cell to prevent infection? A group of biomedical scientists discovered a solution.
Scientists led by Maurizio Pellecchia of the University of California Riverside School of Medicine reported in the journal Molecules that two proteases located on the surface of host cells that are responsible for processing virus invasion-enzymes that break down proteins-can be inhibited. This protease inhibition prevents SARS-CoV2, the coronavirus that causes COVID-19, from invading host cells.
Spike glycoprotein
The outer surface of coronavirus contains an important protein called spike glycoprotein or S-glycoprotein. S-glycoprotein is responsible for giving the coronavirus a typical crown shape, which is essential for virus particles to enter host cells. However, the host cell protease must first process or cut this virus surface protein to allow the virus to enter the cell.
Pellecchia’s laboratory and other researchers have realized that in addition to the previously discovered protease called TMPRSS2, the new SARS-CoV2 coronavirus can also be processed by another human protease called furin. Enter the virus body.
"Processing with the host protease furin is a common mechanism for viral fusion proteins and certain bacterial toxins to enter cells," said Pellecchia, a professor of biomedicine who led the research team. SARS-CoV2 also uses this mechanism. The'proteolytic cleavage' properties of its S-glycoprotein can determine whether the virus can spread across species, such as from bats or camels to humans. "
Fusion proteins combine the properties of more than one protein. Proteolysis refers to the process of breaking the peptide bonds between amino acids in a protein, leading to the cleavage of the protein.
Coronavirus S-glycoprotein contains three cleavage sites processed by human host protease. The exact nature and sequence of these cleavage sites, as well as their respective processing proteases, can determine the level of pathogenicity of the virus and whether it can cross species.
Pellecchia explained that the anthrax toxin similar to SARS-CoV2 needs to be treated with human furin to infect macrophages (a type of white blood cell). Using anthrax toxin as a model system, his team discovered an inhibitor of TMPRSS2 and furin in cell and animal models, which can effectively inhibit the toxin from entering cells.
Recently, a clinical trial for COVID-19 patients started using the TMPRSS2 inhibitor camostat.
"However, we found that camostat is a very poor furin inhibitor," Pellecchia said. "Therefore, our current research calls for the development of more protease inhibitors or inhibitor cocktails that can simultaneously target TMPRSS2 and furin to inhibit SARS-CoV2 from entering host cells."
Pellecchia added that so far, the furin cleavage site in SARS-CoV2 has been associated with enhanced pathogenicity. However, in cell laboratory studies, the gene elimination of furin failed to prevent the virus from entering, indicating that TMPRSS2 is still the most relevant protease.
However, using the peptide sequence of the SARS-CoV2 S-glycoprotein, his team has now proved that the new mutation of this coronavirus strain causes the process of processing the virus invasion by furin and TMPRSS2 to become more efficient and faster. .
"In other words, SARS-CoV2 is different from other less pathogenic strains in that it can more effectively use the proteases TMPRSS2 and furin to initiate host cell invasion," Pellecchia said. "Although TMPRSS2 is more abundant in the lungs, furin is also expressed in other organs, which may explain why SARS-CoV2 can invade and destroy multiple organs."
Pellecchia's laboratory has identified potent and effective furin preclinical inhibitors and proved that these inhibitors can be developed as potential COVID-19 therapeutic drugs, possibly in combination with drugs such as the TMPRSS2 inhibitor camostat.
Pellecchia said: "We are seeking additional funding to design and develop dual inhibitors targeting both TMPRSS2 and furin. This funding will enable us to explore new possible effective therapies against COVID-19 and support research, These studies may have far-reaching applications to avoid future pandemics that may be caused by similar activating mutations in other virus strains."
Source: Bio Valley
