eLife: A coronavirus drug target that can prevent the immune system from shutting down

Structural details of an attractive coronavirus drug target that could be used to combat SARS-CoV-2 and future pandemics
were published today in eLife.

The study revealed a hidden pocket in an important part of the viral mechanism, which is used to evade the immune response, and showed that drugs bound to one of these pockets could stop the virus from replicating
.

One of the proteins known to play a role in SARS-CoV-2 infection is the non-structural protein-1 (Nsp1), but its function is less studied than other parts of the virus, such as the spike protein, which uses the spike protein to enter human cells
.
Nsp1 has been found in several coronaviruses, and its role is to help viruses hijack human protein production mechanisms
.

Alberto Bolsato, a PhD student and first author at the University of Geneva in Switzerland, explains: "It is thought that Nsp1 acts as a gatekeeper, preventing the human host from making important defense proteins while allowing the coronavirus to take over protein production
in its own way.
" "This makes it an attractive antiviral target in principle, but the shape of Nsp1 makes it difficult
to design potential drugs.
" So far, only shallow, superficial cavities have been seen on the surface of Nsp1, which makes it difficult for drugs to attach to and interfere with the function
of Nsp1.
”

To explore whether it was possible to design a drug that targets Nsp1, the team used computational models to study its 3D structure and how it changes shape
under different conditions or when attached to various molecules.
This found 4 previously unidentified bundled bags, two completely hidden and two partially hidden
.

To determine whether these bags could be targeted by drugs, the team conducted an experiment in which they soaked crystalline Nsp1 proteins with 59 different chemical fragments that "attached" to the proteins in computer models
.
To their surprise, only one fragment was bound to Nsp1, in the partially hidden "pocket 1"
.
In further research, they found that the other three bags were masked by crystal contact, which prevented chemical fragments from binding
in crystal immersion experiments.

After discovering the "hitting spot" of pocket 1, they observed whether drugs bound at this location would prevent Nsp1 from interacting with
protein production mechanisms.
In fact, once Nsp1 is in the direction it saw when it binds to the chemical fragment, it can no longer interact
with viral mRNA, the basic messenger molecule that makes proteins.
This suggests that a drug that targets Nsp1's pocket 1 can stop the virus from shutting down the host's immune system
.

Finally, to determine whether these observations apply only to SARS-CoV-2, the research team studied the structure
of the Nsp1 protein of other coronaviruses.
Their computer models showed that ligands that target any pocket in SARS-Cov-2 Nsp1 would also target
corresponding pockets in other coronaviruses tested.
This opens up the possibility
of developing drugs that can prevent future coronavirus pandemics.

"We have described potential drug-binding pockets in the SARS-CoV-2 virus Nsp1 and predicted four partially hidden pockets, one of which we have validated using X-ray crystallography
.
The results of this study can serve as a stepping stone to the design of Nsp1 inhibitors for SARS-CoV-2 and possibly for use in other coronaviruses," concludes
Francesco Luigi Gervasio, Professor of Chemistry and Structural Biology at University College London, UK, and Chair in Biomolecular Modelling.
Gervasio and Carolina Estralas, a postdoctoral researcher at the University of Barcelona in Spain, are co-senior authors
of the study.