With the constant emergence of new variants and the risk of new strains of the virus emerging, developing innovative therapies against SARS-CoV-2 remains a major public health challenge. Currently, proteins 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, has been little studied to date. A team from the University of Geneva (UNIGE), in collaboration with University College London (UCL) and the University of Barcelona, has revealed a hidden ‘pocket’ on its surface. A potential drug target, this cavity opens the way for developing new therapies 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 current treatments – and the possible emergence of new strains of the virus present the risk of new epidemics. Proteins are at the forefront of therapeutic targets to fight the virus. The best known is the spike protein, which is found on the surface of SARS-CoV-2 and gives it its “spiky” appearance. It is key for the virus to enter our cells. It’s the goal of Messenger RNA vaccines.
A little thought-out flagship protein
SARS-CoV-2 also makes other proteins – “non-structural” proteins – using the resources of our cells after it enters. There are sixteen of them. They are necessary for the virus to multiply. Some of them have been studied in the course of developing new drugs. Others have received less attention. This is the case for the Nsp1 protein. Without visible indentations on its surface to hold a potential drug, the researchers felt it couldn’t be a target for treatment.
However, Nsp1 is an important infectious agent for SARS-CoV-2. This small viral protein selectively blocks ribosomes – the protein factories in our cells – making them unusable by our cells and thus inhibiting an immune response. At the same time, via ribosomes, Nsp1 stimulates the production of viral proteins.
Francesco Luigi Gervasio, Full Professor in the Department of Pharmaceutical Sciences and Institute of Pharmaceutical Sciences in Western Switzerland of the UNIGE Faculty of Science, and in the Department of Chemistry and Institute of Structural and Molecular Biology at UCL
Detection by algorithms
Professor Gervasio’s team, in collaboration with UCL and the University of Barcelona, has revealed a “hidden” cavity on the surface of Nsp1, which could be a target for future drugs against SARS-CoV-2. UNIGE Sciences: UNIGE Sciences, first author of the study, explains Alberto Borsato, research and teaching assistant in the Department of Pharmaceutical Sciences and Institute of Pharmaceutical Sciences Western Switzerland, Faculty of Pharmaceutical Sciences in Western Switzerland. Next, in order to confirm the possibility of using this pocket as a drug target, we used experimental screening and X-ray crystallography techniques.
The research team tested several small molecules that could bind to the Nsp1 lumen (experimental screening). She identified one in particular – 5-acetylaminoindane or 2E10 – which also allowed the spatial arrangement of the atoms that make up the cavity to be determined (by crystallography). These are the basic data that form the basis for the development of new drugs.
“These findings pave the way for the development of new therapies that target 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 latest in the study. author. As for the method that was developed to reveal the hidden pocket of Nsp1, it can be used to discover new cavities on the surface of other proteins that are still unknown to scientists.
Borsato, A.; et al. (2022) Detection of encoded drug-consuming pockets in Nsp1 of SARS-CoV-2 and other coronaviruses by simulation and crystallography. eLife. doi.org/10.7554/eLife.81167.