With the continued emergence of new variants and the risk of new virus strains, the development of innovative therapies against SARS-CoV-2 remains a major public health challenge. Currently, proteins found on the surface of the virus and/or involved in its replication are the preferred therapeutic targets, such as the Spike protein targeted by vaccines. One of them, the non-structural protein Nsp1, had been little studied until now. A team from the University of Geneva (UNIGE), in collaboration with University College London (UCL) and the University of Barcelona, has now revealed the existence of a hidden “pocket” on its surface. This cavity, a potential pharmacological target, opens the way to the development of new treatments against Covid-19 and other coronaviruses. These results can be found in the journal eLife.
The rapid rollout of new vaccines and antiviral drugs has helped contain the Covid-19 pandemic, caused by the SARS-CoV-2 virus. Despite the advances, the development of new therapies remains an urgent priority: the continuous appearance of new variants -some of them resistant to current treatments- and the possible appearance of new strains of the virus pose a risk of new pandemics. Proteins are at the forefront of therapeutic targets to combat the virus. The best known is the Spike protein, which is found on the surface of SARS-CoV-2 and gives it its “spike” appearance. It is the key for the virus to enter our cells. It is the target of messenger RNA vaccines.
An understudied key protein
SARS-CoV-2 also makes other proteins, the “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 studied in the context of new drug development. Others have received less attention. This is the case of the Nsp1 protein. With no obvious cavities in its surface to anchor a potential drug, the researchers felt it could not be a target for treatment.
However, Nsp1 is an important infectious agent of SARS-CoV-2. This small viral protein selectively blocks ribosomes, the protein factories of our cells, making them unusable for our cells and thus preventing the immune response. At the same time, through the ribosomes, Nsp1 stimulates the production of viral proteins.”
Francesco Luigi Gervasio, Full Professor of the Section of Pharmaceutical Sciences and the Western Swiss Institute of Pharmaceutical Sciences of the UNIGE Faculty of Sciences, and the Department of Chemistry and the Institute of Structural and Molecular Biology of UCL
Revealed by algorithms
Professor Gervasio’s team, in collaboration with UCL and the University of Barcelona, has revealed the existence of a “hidden” cavity on the surface of Nsp1, which could be the target of future drugs against SARS-CoV -two. “To uncover this cryptic and partially hidden pocket, we ran simulations using algorithms we developed,” explains Alberto Borsatto, research and teaching assistant at the Section of Pharmaceutical Sciences and the West Swiss Institute of Pharmaceutical Sciences at the UNIGE Faculty of Sciences. , first author of the study. “Next, to confirm that this pocket could be used as a drug target, we used experimental detection techniques and X-ray crystallography.”
The research team tested many small molecules that could potentially bind to the Nsp1 pocket (experimental detection). He identified one in particular, 5-acetylaminoindane or 2E10, which also made it possible to determine the spatial arrangement of the atoms that make up the cavity (by crystallography). These are essential data that form the basis for the development of new drugs.
“These results pave the way for the development of new treatments targeting the Nsp1 protein, not only against SARS-CoV-2 and its variants, but also against other coronaviruses in which Nsp1 is present,” says Francesco Luigi Gervasio, last of the study. Author. As for the method developed to reveal the hidden pocket of Nsp1, it could be used to discover, on the surface of other proteins, new cavities still unknown to scientists.
Borsato, A. et al. (2022) Revealing cryptic pharmacological pockets in Nsp1 of SARS-CoV-2 and other β-coronaviruses using simulations and crystallography. eLife. doi.org/10.7554/eLife.81167.
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