COVID-19: Drug targets enzymes that permit virus to invade cells
SARS-CoV-2, the virus that triggers COVID-19, enlists the assistance of two enzymes on the surface of human cells in order to invade them. A fresh study suggests that a compound that inhibits both enzymes could make an efficient treatment.
When disease-causing viruses break right into their hosts’ cells, it really is invariably an “inside job.” Viral pathogens can only just invade cells and replicate with the help of the cells’ own molecular machinery.
SARS-CoV-2 is no exception. Prior to the new coronavirus can enter a human cell, enzymes called proteases on the cell’s surface must split open the protein spikes that provide the virus its characteristic crown-like appearance.
This splitting changes the condition of the spikes, exposing the binding sites that permit the virus to get entry to the cell.
The spikes of coronaviruses contain three “cleavage sites,” where particular proteases can split the proteins. A coronavirus can, therefore, only invade cells that bear the appropriate proteases.
The cleavage sites and their respective proteases help regulate how pathogenic the virus is, which tissues it could infect, and whether it could jump from species to species.
Scientists at the University of California, Riverside’s School of Medicine and the Sanford Burnham Prebys Medical Discovery Institute, in La Jolla, wanted to learn whether a compound that inhibits two particular proteases would protect cells from invasion by SARS-CoV-2.
Their findings have already been published in the journal Molecules.
A previous study had suggested that among the proteases, called furin, is employed by some of the most pathogenic coronaviruses. It can be one factor that helps SARS-CoV-2 spread so easily.
Anthrax model
Instead of working directly with SARS-CoV-2, the researchers used anthrax toxin as a model.
Simply because furin not only helps viruses infect cells, in addition, it activates anthrax toxin, and can enter and kill cells.
Crucially, furin cleaves the same sequence of peptides - the units that form protein - in both SARS-CoV-2 spike protein and the anthrax toxin. This makes the toxin an excellent model.
First, the researchers checked whether their agent, called compound 1, could protect human cells in a dish from the toxin.
Once they confirmed this, they continued to investigate whether compound 1 would protect mice from the toxin.
They discovered that even a single dose of the compound considerably improved the animals’ survival.
Dual action
Compound 1 inhibits both furin and another protease, called TMPRSS2.
Within their paper, the scientists argue that further research is required to develop compounds like theirs that inhibit both proteases, instead of just one single. Alternatively, a cocktail of different protease inhibitors could also work, they argue.
The analysis authors cite two lines of evidence because of their argument.
First, when scientists during the past have genetically engineered host cells in order that they were struggling to make furin, it has didn't stop the virus from infecting the cells.
Second, when the authors of today's study viewed the peptide sequence of the SARS-CoV-2 spike protein, they found evidence that newly acquired mutations permit the virus to exploit both furin and TMPRSS2 cleavage sites.
These mutations have given the virus the opportunity to infect a wider variance of tissues in your body.
“In other words, SARS-CoV-2, unlike other, less pathogenic strains, can more proficiently use both proteases, TMPRSS2 and furin, to get started on the invasion of host cells,” says Maurizio Pellecchia, a professor of biomedical sciences at the University of California, Riverside, who led the research team.
“While TMPRSS2 is more abundant in the lungs, furin is expressed in other organs, perhaps explaining why SARS-CoV-2 is capable of invading and damaging multiple organs.”
Source: www.medicalnewstoday.com
