While vaccines can lead the world toward post-pandemic normality, a conversion of SARS-CoV-2 requires the progression of effective drugs. The Institut Pasteur in France and the National Institutes of Health (NIH) in the United States, propose a new healing technique to combat the infamous virus. Instead of targeting the virus’s culprit viral protein entering the cell, the study team analyzed the protein in the membrane of our cells that allows this entry. Using a complex synthetic evolution technique they developed, the researchers generated a molecular ‘super cork’ that physically blocks this ‘port of entry’, preventing the virus from sticking in and entering the cell.
Most prospective treatments (and existing vaccines) for SARS-CoV-2 target the so-called “advanced protein” discovered in the outer layer of the virus. However, this protein is prone to mutations that erode the effectiveness of those treatments. “the virus is evolving, instead we focus on the non-evolutionary human receptor called ACE2, which acts as the access site for the virus,” says Professor Gideon Schreiber of Weizmann’s Department of Biomolecular Sciences, who oversaw the new study. not sensitive to new emerging viral variants, which is one of the most demanding situations in the fight against the pandemic.
Prof. Gideon Schreiber. A new treatment for COVID-19 evolved through synthetic evolution
ACE2, attached to the membrane of lung epithelial cells and other tissues, is a vital enzyme for regulating blood pressure. Therefore, as tempting as it is to block this receptor to prevent access by SARS-CoV-2, like Schreiber, whose lab specializes in the analysis of protein interactions, set out to expand a small protein molecule that can also bind to ACE2 more than SARS-CoV-2 but without affecting the enzyme. receptor activity.
The researchers, led by Dr. Jiří Zahradník, a postdoctoral researcher in Schreiber’s group, began by identifying the binding domain of SARS-CoV-2: the relatively short series of building blocks within the largest complex protein that physically binds to ACE2. The virus receptor binding domain itself as an opposite weapon to it, Zahradník carried out several series of “evolution in a control tube”, developed in Schreiber’s laboratory, in a genetically modified strain of baker’s yeast. As yeast can be handled without problems, Zahradník was able to temporarily analyze millions of other mutations that have accumulated this synthetic evolution, a procedure that mimics herbal evolution at a much faster rate. Ultimately, the purpose was to locate a small molecule that was particularly “sticky” than the original viral version.
During this research process, Schreiber’s team provided solid evidence to aid speculation that SARS-CoV-2 becomes more contagious when mutations are compatible with CEA2. The researchers found that already after the first selection circular, laboratory-made variants with binding functions closer to ACE2 mimicked mutations in the binding domain names of the maximum contagious SARS-CoV-2 strains that had occurred through herbal evolution, such as the British variant (Alpha), the South African variant (Beta) and the Brazilian variant (Gamma) Surprisingly, the now extended Indian variant (Delta) relies on another trick to be more contagious: partially escape detection through the immune system.
Structure of an ACE2 receptor (left), the binding molecule (top right) and the new
Finally, Zahradník removed a small fragment of protein with a binding capacity a thousand times more powerful than that of the original binding domain from which it evolved. This “super cork” not only went to ACE2 like a glove, but was also discovered through Maya Shemesh and Shir Marciano, PhD fellows in Schreiber’s lab, to maintain the enzymatic activity of ACE2, as the researchers had predicted. In addition, due to the strong bonding, very low concentrations of the newly changed molecule were needed to achieve the desired blocking effect. .
To expand the possibility of administering the molecule as a drug, Schreiber and his team collaborated with Professor Yinon Rudich of Weizmann’s Department of Earth and Planetary Sciences. In collaboration with Dr. Ira Marton and Dr. Chunlin Li, they created an aerosol spray. which would allow the molecule evolved by inhalation to be administered to patients.
So far, NIH researchers have tested formulas developed in hamsters inflamed with SARS-CoV-2 Preliminary effects imply that this remedy particularly reduces the symptoms of the disease, suggesting that it would possibly be a prospective drug. planned at the NIH in the near future.
Looking for a “super cork” that would block the ACE2 receptor, the researchers tested about 1,000,000,000 mutant yeasts.
Professor Gideon Schreiber’s studies are supported by the Ben B Foundation. And Joyce E. Eisenberg; the confidence of the circle of relatives René and Tillie Molho; Botton Honey; and the Yotam project.