Posted
MedicinalDiscovery of a new target to attack the coronavirus
An international team, including from the University of Geneva, has found a possible weakness in a protein other than Spike on the surface of the virus.
The Spike protein gives SARS-Cov2 its pointed shape, but it’s not the only one present on the surface.
Getty Images/iStockphoto
The rapid deployment of new vaccines and new antiviral drugs has helped stem the COVID-19 pandemic, caused by the SARS-CoV-2 virus. Despite the progress made, the development of new therapies remains imperative, explains the University of Geneva (UNIGE) in a press release. The regular appearance of new variants, some of which are resistant to available treatments, and the possible emergence of new strains of the virus represent a risk of new pandemics.
To fight the virus, proteins are at the forefront of therapeutic targets. The best known is the Spike protein, which is found on the surface of SARS-CoV-2 and gives it its “spiky” appearance. It is the key that allows the virus to enter our cells. This is the goal of messenger RNA vaccines.
An understudied key protein
But SARS-CoV-2 also produces other so-called “non-structural” proteins, using the resources of our cells after entering them. There are sixteen of them. They are essential for virus replication. Some have been extensively studied in the development of new drugs. Others have received less attention. This is the case of the Nsp1 protein. Due to the lack of obvious cavities on its surface for anchoring a potential drug, scientists believed it could not be a target for treatments.
“Nsp1 is in any case an important infectious agent of SARSCoV-2, explains Francesco Luigi Gervasio, professor at the UNIGE Faculty of Science and at the Department of Chemistry and at the Institute of Structural and Molecular Biology of University College London (UCL ). This small viral protein selectively blocks the ribosomes (ie the protein factories of our cells) making them unusable by our cells and thus preventing the immune response. At the same time, through ribosomes, Nsp1 stimulates the production of viral proteins.”
Revealed by algorithms
This was revealed today, in a study published in the journal, by Professor Gervasio’s team, in collaboration with UCL and the University of Barcelona “Electronic Life”, the existence of a “hidden” cavity on the surface of Nsp1, which could be the target of future drugs against SARS-CoV-2. “To uncover this partially hidden pocket, we carried out simulations using algorithms we developed,” explains Alberto Borsatto, assistant professor at UNIGE’s Faculty of Sciences, first author of the study. . “Then, to confirm that this pocket could be used as a drug target, we used experimental screening and X-ray crystallography techniques.”
The research team then tested a large number of small molecules that could potentially bind to the cavity of Nsp1 (experimental screening). He identified one in particular, called 5 acetylaminoindan or 2E10, which also made it possible to determine (by crystallography) the spatial arrangement of the atoms that make up the cavity. Essential data that forms the basis of the new drug development process.
Possible new treatments
“These results pave the way for the development of new treatments targeting the Nsp1 protein, not only to fight SARS-CoV-2 and its variants but also against other coronaviruses for which Nsp1 is present”, exults Francesco.Luigi Gervasio. As for the method developed to reveal the hidden pocket of Nsp1, it can be used to discover, on the surface of other proteins, new cavities still unknown to scientists.
