Research reveals the presence of a hidden “pocket” on the surface of a key SARS-CoV-2 protein

With the constant emergence of new variants and the threat of new strains of the virus, the development of innovative treatments against SARS-CoV-2 remains a major public health challenge. Currently, the proteins that are on the surface of the virus and/or involved in its replication are 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. A potential drug target, this hole 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 spread of new vaccines and antiviral drugs has helped contain the Covid-19 pandemic, caused by the SARS-CoV-2 virus. Despite the progress made, the development of new treatments remains an urgent priority: the constant emergence of new variants – some of which are resistant to existing treatments – and the possible appearance of new strains of the virus pose the risk of a new pandemic. Proteins are at the forefront of therapeutic targets to fight the virus. The best known is the Spike protein, which is located on the surface of SARS-CoV-2 and gives it its “spiky” appearance. It is the key to the virus entering our cells. It is the target of messenger RNA vaccines.

A little-studied key protein

SARS-CoV-2 also produces other proteins – the “non-structural” proteins – using the resources of our cells after entering them. There are sixteen of them. They are necessary for virus replication. Some have been studied in connection with the development of new drugs. Others have received less attention. This is the case for the Nsp1 protein. With no obvious cavities on its surface to trap a potential drug, researchers thought it might not be a therapeutic target.

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 by our cells and thus preventing an immune response. At the same time, with ribosomes, Nsp1 stimulates the production of viral proteins.”

Francesco Luigi Gervasio, Professor at the Department of Pharmacology and the Institute of Pharmaceutical Sciences of Western Switzerland at the UNIGE Faculty of Science, and at the Department of Chemistry and the Institute of Structural and Molecular Biology at UCL

Illustrated with algorithms

Professor Gervasio’s team, in collaboration with UCL and the University of Barcelona, ​​uncovered the presence of a “hidden” cavity on the surface of Nsp1, which could be the target of future drugs against SARS-CoV-2. ”To uncover this cryptic, partially hidden pocket, we performed simulations with algorithms we developed,” explains Alberto Borsatto, research and teaching assistant at the Faculty of Pharmacy and the Institute of Pharmacology of Western Switzerland at the department. Sciences of the UNIGE, 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 crystallographic techniques.”

The research team tested many small molecules that could potentially bind to the Nsp1 cavity (experimental screening). It identified one in particular – 5 acetylaminoindene or 2E10 – which also allowed the spatial arrangement of the atoms making up the cavity to be determined (by crystallization). This is essential data that forms the basis for the development of new drugs.

“These results pave the way for the development of new therapies targeting the Nsp1 protein, not only against SARS-CoV-2 and its variants, but also against other coronaviruses where Nsp1 is present,” says Francesco Luigi Gervasio, the last investigator 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 that are not yet known to scientists.

Source:

Diary reference:

Borsatto, A., and more. (2022) Uncovering drug-free cryptic pockets in Nsp1 of SARS-CoV-2 and other β-coronaviruses by simulation and crystallization. eLife. doi.org/10.7554/eLife.81167.

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