Synthesis and In Vitro Evaluation of C-7 and C-8 Luteolin Derivatives as Influenza Endonuclease Inhibitors

0556294 - ÚMG 2022 RIV CH eng J - Článek v odborném periodiku
Reiberger, R. - Radilova, K. - Král, M. - Zima, V. - Majer, P. - Brynda, Jiří - Dračínský, M. - Konvalinka, J. - Kožíšek, M. - Machara, A.
Synthesis and In Vitro Evaluation of C-7 and C-8 Luteolin Derivatives as Influenza Endonuclease Inhibitors.
International Journal of Molecular Sciences. Roč. 22, č. 14 (2021), č. článku 7735. E-ISSN 1422-0067
Institucionální podpora: RVO:68378050
Klíčová slova: bio-isosterism * cross-coupling * endonuclease inhibitor * flavonoids * influenza * Mannich reaction * RNA polymerase
Obor OECD: Biochemistry and molecular biology
Impakt faktor: 6.208, rok: 2021
Způsob publikování: Open access
https://www.mdpi.com/1422-0067/22/14/7735

The part of the influenza polymerase PA subunit featuring endonuclease activity is a target for anti-influenza therapies, including the FDA-approved drug Xofluza. A general feature of endonuclease inhibitors is their ability to chelate Mg2+ or Mn2+ ions located in the enzyme's catalytic site. Previously, we screened a panel of flavonoids for PA inhibition and found luteolin and its C-glucoside orientin to be potent inhibitors. Through structural analysis, we identified the presence of a 3 ',4 '-dihydroxyphenyl moiety as a crucial feature for sub-micromolar inhibitory activity. Here, we report results from a subsequent investigation exploring structural changes at the C-7 and C-8 positions of luteolin. Experimental IC50 values were determined by AlphaScreen technology. The most potent inhibitors were C-8 derivatives with inhibitory potencies comparable to that of luteolin. Bio-isosteric replacement of the C-7 hydroxyl moiety of luteolin led to a series of compounds with one-order-of-magnitude-lower inhibitory potencies. Using X-ray crystallography, we solved structures of the wild-type PA-N-terminal domain and its I38T mutant in complex with orientin at 1.9 angstrom and 2.2 angstrom resolution, respectively.
Trvalý link: http://hdl.handle.net/11104/0330581