November 23, 2022 -- A University of Geneva (UNIGE)-led research team revealed a hidden cavity on the surface of a key non-structural SARS-CoV-2 protein. Their research, published November 22 in the journal eLife, may facilitate this cavity’s use as a target for binding therapeutic drugs.
With new variants continuously emerging, developing innovative therapies against SARS-CoV-2 remains a public health challenge. Currently, the virus's surface proteins -- such as the spike protein -- are preferred therapeutic targets. But SARS-CoV-2 also uses the cells' resources after entering them to create 16 non-structural proteins essential for its replication. One such protein, Nsp1, had previously been little studied. Although an important infectious agent, Nsp1 lacked obvious surface cavities upon which to anchor potential drugs.
Using algorithms, the researchers carried out simulations to uncover the cryptic, partially hidden pocket on Nsp1's surface. After experimentally screening many small molecules that could potentially bind to the Nsp1 cavity, they identified one -- 5 acetylaminoindane or 2E10 -- that also allowed the spatial arrangement of the atoms making up the cavity to be determined by x-ray crystallography, confirming that this pocket was a viable drug target.
In infected cells, Nsp1 acts as a "cork" that prevents the host's mRNA expression. The binding of a ligand to Nsp1's cryptic pocket could prevent this blockage and recover the ribosome's ability to initiate mRNA translation. Researchers contend that the method developed to discover the hidden Nsp1pocket could help reveal still-unknown cavities on the surfaces of other proteins.
"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,'' UNIGE co-author Francesco Luigi Gervasio, PhD, said in a statement.