Covid, found the target protein that can block the virus
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The mechanisms that SARS-CoV-2 uses to enter our body and hit it in the weakest parts are known. Less so are those that allow it to be blocked, together with drugs capable of at least reducing its extent. It is on this front that a team of US researchers has moved. The result was the identification of a target and a potential drug capable of blocking the spread of the virus.
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Find new viral strategies
The study by American experts, published in Nature Communications, indicates that a ‘chaperone’ protein (functional class of protein families, whose predominant function is the prevention of incorrect associations and aggregation of unfolded polypeptide chains) known as GRP78, plays an essential role in the spread of SARS-CoV-2 . Starting from a premise: “This pandemic highlights the urgent need to identify new antiviral strategies, including drugs that target the host side”. The researchers recall that “coronaviruses impose multiple functional, but also structural changes to a wide range of cellular pathways and there is growing evidence that some of these pathways can be exploited therapeutically”.
How the virus penetrates the cells
But how does the SARS-CoV-2 virus penetrate host cells? It does this thanks to its special Spike receptors which allow it to recognize those to be infected, to adhere to their surface and subsequently to enter and reproduce. Spike glycoproteins bind to particular receptors present on the plasma membrane of some cells. For the SARS-CoV-2 virus, the receptor of choice is the enzyme that converts angiotensin (the ACE2 receptor), a protein essential for regulating blood pressure, and which is present in the cells of many tissues in our body. This binding allows the virus to enter cells easily.
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The ‘virus factory’
Upon binding, the viral protein S splits into two parts: S1, which binds to the target cell’s ACE2 receptor, and S2, which allows the virus to enter the cell. The SARS-CoV-2 viral particles enter cells and release the virus genome (RNA) into the cytoplasm. The viruses, once inside, release their genome and transform the cell into a ‘virus factory’. In fact, with their parasitic behavior they are able to use all the replicative apparatus of the host cell managing to reproduce their RNA and all the viral proteins that are used to form the new viruses, which, numerous, will be assembled inside the cell up to causing their death with the release of the new SARS-CoV-2 viral particles. These will then be able to infect other cells and, above all, other individuals.
The protein that hijacks the virus
Researchers had previously shown that when SARS-CoV-2 infection occurs, the GRP78 protein, which normally helps regulate the folding of other cellular proteins, is hijacked to work with other cellular receptors to bring the virus to life. inside the cells, where it can then reproduce and spread. “However, questions remained as to whether it was necessary and essential for SARS-CoV-2 to replicate within human lung cells,” he explains. Amy Leeof the Keck School of Medicine at the University of Southern California, Los Angeles, senior author of the study.
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What the study shows
By examining human lung epithelial cells infected with the virus, the research team observed that as the viral infection intensified, the infected cells produced higher levels of GRP78. Then the experts used messenger RNA to suppress the production of the GRP78 protein in human lung epithelial cells in cell culture, without disrupting other cellular processes.
The cells were subsequently infected with SARS-CoV-2, and produced less of the viral spike protein, releasing far less material capable of infecting others. All of this demonstrated that the GRP78 protein is necessary and essential for viral replication and production.
The lung test
At this point it was a question of better understanding whether GRP78 could represent the right hookup to treat Covid. For this the researchers tested on infected lung cells the recently identified small molecule drug HA15, which specifically binds to GRP78 and inhibits its activity, a drug developed for use against cancer cells.
The result was promising: the medicine proved to be very effective in reducing the number and size of SARS-CoV-2 produced in infected cells, and at the same time did not generate harmful effects on normal ones. The team then tested HA15 on mice genetically engineered to express a human SARS-CoV-2 receptor and infected them with the virus, finding that the drug markedly reduced the viral load in their lungs. “These and other GRP78 inhibitors will be tested as treatments for Covid – conclude the authors -. And they may also prove useful in blocking future coronaviruses that depend on GRP78 for entry and replication.”
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