To develop novel inhibitors for viruses with pandemic potential, we have turned our attention towards targeting their helicases due to their high sequence conservation and essential role in viral replication (Newman et al., Nature communications, 2021). SARS-CoV-2 is especially interesting as its helicase, NSP13, was determined to have druggable binding pockets, some of which are highly conserved (Newman et al., Nature communications, 2021). Since helicases share similar structure and function there is reason to believe that established inhibitors of human helicases can be repurposed or used at a starting point to design novel antivirals.
In this post, we analyzed a human helicase structure, in complex with an inhibitor, to see whether it can inspire a design for a viral inhibitor. We have superimposed the crystal structure of the BRR2 RNA helicase, SNRNP200 (PDB ID 5URK) bound to an allosteric inhibitor, onto SARS-CoV-2 NSP13 helicase (PDB ID 7RDY). Unfortunately, we found that the N- and C-terminal helicase domains of both helicases do not superimpose well. The allosteric inhibitor in SNRNP200 requires the Sec63 domain to bind to the protein. However, this domain is not present in SARS-CoV-2. Therefore, it is highly unlikely this allosteric inhibitor will bind to SARS-CoV-2.
Full-screen ICM analysis can be found here.
Citations:
Fernandez, A. J., & Berger, J. M. (2021). Mechanisms of hexameric helicases. Critical Reviews in Biochemistry and Molecular Biology, 56(6), 621–639. https://doi.org/10.1080/10409238.2021.1954597
Newman, J. A., Douangamath, A., Yadzani, S., Yosaatmadja, Y., Aimon, A., Brandão-Neto, J., Dunnett, L., Gorrie-stone, T., Skyner, R., Fearon, D., Schapira, M., von Delft, F., & Gileadi, O. (2021). Structure, mechanism and crystallographic fragment screening of the SARS-CoV-2 NSP13 helicase. Nature Communications, 12(1), 4848. https://doi.org/10.1038/s41467-021-25166-6