Antiviral activity of natural phenolic compounds in complex at an allosteric site of SARS-CoV-2 papain-like protease.
Srinivasan, V., Brognaro, H., Prabhu, P.R., de Souza, E.E., Gunther, S., Reinke, P.Y.A., Lane, T.J., Ginn, H., Han, H., Ewert, W., Sprenger, J., Koua, F.H.M., Falke, S., Werner, N., Andaleeb, H., Ullah, N., Franca, B.A., Wang, M., Barra, A.L.C., Perbandt, M., Schwinzer, M., Schmidt, C., Brings, L., Lorenzen, K., Schubert, R., Machado, R.R.G., Candido, E.D., Oliveira, D.B.L., Durigon, E.L., Niebling, S., Garcia, A.S., Yefanov, O., Lieske, J., Gelisio, L., Domaracky, M., Middendorf, P., Groessler, M., Trost, F., Galchenkova, M., Mashhour, A.R., Saouane, S., Hakanpaa, J., Wolf, M., Alai, M.G., Turk, D., Pearson, A.R., Chapman, H.N., Hinrichs, W., Wrenger, C., Meents, A., Betzel, C.(2022) Commun Biol 5: 805-805
- PubMed: 35953531
- DOI: https://doi.org/10.1038/s42003-022-03737-7
- Primary Citation of Related Structures:
7NFV, 7OFS, 7OFT, 7OFU - PubMed Abstract:
SARS-CoV-2 papain-like protease (PLpro) covers multiple functions. Beside the cysteine-protease activity, facilitating cleavage of the viral polypeptide chain, PLpro has the additional and vital function of removing ubiquitin and ISG15 (Interferon-stimulated gene 15) from host-cell proteins to support coronaviruses in evading the host's innate immune responses. We identified three phenolic compounds bound to PLpro, preventing essential molecular interactions to ISG15 by screening a natural compound library. The compounds identified by X-ray screening and complexed to PLpro demonstrate clear inhibition of PLpro in a deISGylation activity assay. Two compounds exhibit distinct antiviral activity in Vero cell line assays and one inhibited a cytopathic effect in non-cytotoxic concentration ranges. In the context of increasing PLpro mutations in the evolving new variants of SARS-CoV-2, the natural compounds we identified may also reinstate the antiviral immune response processes of the host that are down-regulated in COVID-19 infections.
Organizational Affiliation:
Department of Chemistry, Institute of Biochemistry and Molecular Biology, Laboratory for Structural Biology of Infection and Inflammation, Universität Hamburg, Build. 22a, c/o DESY, 22607, Hamburg, Germany. vasundara.srinivasan@chemie.uni-hamburg.de.