Unraveling the anti-influenza effect of flavonoids: Experimental validation of luteolin and its congeners as potent influenza endonuclease inhibitors

0539161 - ÚMG 2021 RIV FR eng J - Článek v odborném periodiku
Zima, V. - Radilova, K. - Kožíšek, M. - Albinana, C. B. - Karlukova, E. - Brynda, Jiří - Fanfrlik, J. - Flieger, M. - Hodek, J. - Weber, J. - Majer, P. - Konvalinka, J. - Machara, A.
Unraveling the anti-influenza effect of flavonoids: Experimental validation of luteolin and its congeners as potent influenza endonuclease inhibitors.
European Journal of Medicinal Chemistry. Roč. 208, December (2020), č. článku 112754. ISSN 0223-5234. E-ISSN 1768-3254
Institucionální podpora: RVO:68378050
Klíčová slova: Influenza * Neuraminidase * Polyphenols * PA(N) endonuclease Inhibitors * RNA polymerase
Obor OECD: Biochemistry and molecular biology
Impakt faktor: 6.514, rok: 2020
Způsob publikování: Open access
https://www.sciencedirect.com/science/article/pii/S0223523420307261?via%3Dihub

The biological effects of flavonoids on mammal cells are diverse, ranging from scavenging free radicals and anti-cancer activity to anti-influenza activity. Despite appreciable effort to understand the anti-influenza activity of flavonoids, there is no clear consensus about their precise mode-of-action at a cellular level. Here, we report the development and validation of a screening assay based on AlphaScreen technology and illustrate its application for determination of the inhibitory potency of a large set of polyols against PA N-terminal domain (PA-Nter) of influenza RNA-dependent RNA polymerase featuring endonuclease activity. The most potent inhibitors we identified were luteolin with an IC50 of 72 +/- 2 nM and its 8-C-glucoside orientin with an IC50 of 43 +/- 2 nM. Submicromolar inhibitors were also evaluated by an in vitro endonuclease activity assay using single-stranded DNA, and the results were in full agreement with data from the competitive AlphaScreen assay. Using X-ray crystallography, we analyzed structures of the PA-Nter in complex with luteolin at 2.0 angstrom resolution and quambalarine B at 2.5 angstrom resolution, which clearly revealed the binding pose of these polyols coordinated to two manganese ions in the endonuclease active site. Using two distinct assays along with the structural work, we have presumably identified and characterized the molecular mode-of-action of flavonoids in influenza-infected cells. (c) 2020 The Author(s). Published by Elsevier Masson SAS. This is an open access article under the CC BYNC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Trvalý link: http://hdl.handle.net/11104/0316866