Research reveals the existence of a hidden ”pocket” on the surface of the main SARS-CoV-2 protein

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, the proteins located 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 these, the nonstructural 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 the surface. This cavity, a potential drug 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 antivirals has helped contain the Covid-19 pandemic caused by the SARS-CoV-2 virus. Despite the progress made, the development of new therapies is still an urgent priority: the continued emergence of new variants – some of which are resistant to current treatments – and the possible emergence of new virus strains pose a risk of new pandemics. Proteins are at the forefront of therapeutic targets to fight the virus. The best known is the Spike protein, which resides 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 makes other proteins – the “non-structural” proteins – using our cells’ resources after entering them. There are sixteen. They are essential for the replication of the virus. Some have been studied in the context of new drug development. Others have received less attention. This is the case with the Nsp1 protein. With no obvious voids on the surface to anchor a potential drug, researchers felt it couldn’t be a target for treatment.

However, Nsp1 is a major infectious agent of SARS-CoV-2. This small viral protein selectively blocks ribosomes – our cells’ protein factories – rendering them useless to our cells and thus inhibiting the immune response. At the same time, Nsp1 stimulates the production of viral proteins via ribosomes.”

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

Revealed by algorithms

Professor Gervasio’s team, in collaboration with UCL and the University of Barcelona, ​​revealed the existence of a ”hidden” pocket 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 ran simulations using algorithms we developed,” explains Alberto Borsatto, research and teaching assistant at the Department of Pharmaceutical Sciences and the Institute of Pharmaceutical Sciences of West Switzerland from the Faculty of Pharmaceutical Sciences. Sciences of the UNIGE, first author of the study. “Once we confirmed that this pocket could be used as a drug target, we used experimental screening and X-ray crystallography techniques.”

The research team tested many small molecules that could potentially bind to the Nsp1 pocket (experimental screening). It identified one in particular – 5 acetylaminoindane or 2E10 – which also enabled the determination of 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 medicines.

“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, the last of the study. author. As for the method developed to reveal Nsp1’s hidden pocket, it could be used to discover new pockets on the surface of other proteins that scientists are not yet aware of.

Source:

Magazine reference:

Borsatto, A., et al. (2022) Unveiling of drugpable cryptic pockets in the Nsp1 of SARS-CoV-2 and other β-coronaviruses through simulations and crystallography. eLife. doi.org/10.7554/eLife.81167.

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