The latest research shows that the SARS-CoV-2 spike protein is no longer the only target

With the emergence of new variants and the risk of new strains, the development of innovative therapeutics against SARS-CoV-2 remains a major public health challenge
.
Currently, proteins on the viral surface and/or involved in viral replication are the preferred therapeutic targets, such as vaccine-targeted spike proteins
.
Among them, the non-structural protein Nsp1 has rarely been studied
before.
A team of researchers from the University of Geneva (UNIGE), in collaboration with University College London (UCL) and the University of Barcelona, discovered the existence
of hidden "pockets" on its surface.
This hole is a potential drug target, opening the way
for the development of new therapies 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 progress, the development of new treatments remains an urgent priority: the emergence of new variants – some resistant to current treatments – and the emergence of new strains of the virus pose the risk of
new pandemics.
Proteins are cutting-edge therapeutic targets against viruses
.
The most famous is the spike protein, which is located on the surface of SARS-CoV-2, giving it a "spiny" appearance
.
It is the key for the
virus to enter our cells.
It is a target for messenger RNA
vaccines.

This is a key protein that has been studied less

SARS-CoV-2 also uses cellular resources to make other proteins – "non-structured" proteins
– after entering the cell.
There are sixteen of them
.
They are necessary for
virus replication.
Some have already been studied
in the context of new drug development.
Others receive less attention
.
This is the case with
the Nsp1 protein.
Because there are no obvious cavities on its surface to fix the underlying drug, the researchers believe it is unlikely to be a therapeutic target
.

"However, Nsp1 is an important infectious agent of SARS-CoV-2," explains
Francesco Luigi Gervasio, full professor at the Department of Pharmaceutical Sciences at the Faculty of Science at UNIGE and the West Swiss Institute of Pharmaceutical Sciences, the Department of Chemistry and the Institute of Structural and Molecular Biology at University College London.
"This small viral protein selectively blocks ribosomes — the protein factories of our cells — making them unusable by our cells, thereby blocking the immune response
.
At the same time, through ribosomes, Nsp1 stimulates the production
of viral proteins.
”

Algorithm reveals

Professor Gervasio's team, working with University College London and the University of Barcelona, has revealed a "hidden" void on the surface of Nsp1, which could be the target
of future anti-SARS-CoV-2 drugs.
"To discover this mysterious, partially hidden pocket, we simulated it using an algorithm we developed," explains Alberto Borsatto, first author of the study and research and teaching assistant
at the Institute of Pharmaceutical Sciences and the Department of Pharmaceutical Sciences in Western Switzerland, at the United Nations Higher Education Institute.
"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 tested a number of small molecules that could bind to the Nsp1 cavity (experimental screening).

It specifically determines one - 5 acetaminoindene or 2E10 - which also allows to determine the spatial arrangement of the atoms that make up the cavity (by crystallography).

This basic data forms the basis for the development of
new drugs.

Francesco Luigi Gervasio, the last author of the study, said: "These results pave the way for the development of new treatments against the Nsp1 protein, not only SARS-CoV-2 and its variants, but also other coronaviruses
where Nsp1 is present.
" As for the method developed to reveal the hidden pockets of Nsp1, it could be used to find new cavities
on the surface of other proteins that scientists don't yet know about.