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

0544040 - ÚOCHB 2022 RIV CH eng J - Journal Article
Reiberger, Róbert - Radilová, Kateřina - Král, Michal - Zima, Václav - Majer, Pavel - Brynda, Jiří - Dračínský, Martin - Konvalinka, Jan - Kožíšek, Milan - Machara, Aleš
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
R&D Projects: GA MŠMT(CZ) EF16_019/0000729; GA MŠMT(CZ) LM2018133
Institutional support: RVO:61388963
Keywords : bio-isosterism * cross-coupling * endonuclease inhibitor * flavonoids * influenza * Mannich reaction * RNA polymerase
OECD category: Biochemistry and molecular biology
Impact factor: 6.208, year: 2021
Method of publishing: Open access
https://doi.org/10.3390/ijms22147735

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 Å and 2.2 Å resolution, respectively.
Permanent Link: http://hdl.handle.net/11104/0321100