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.

• Klíčová slova
• Mannich reaction, RNA polymerase, bio-isosterism, cross-coupling, endonuclease inhibitor, flavonoids, influenza,
• MeSH
• antivirové látky chemická syntéza   farmakologie   MeSH
• endonukleasy antagonisté a inhibitory   MeSH
• katalytická doména účinky léků   MeSH
• luteolin chemická syntéza   farmakologie   MeSH
• Orthomyxoviridae účinky léků   MeSH
• virové proteiny antagonisté a inhibitory   MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antivirové látky MeSH
• endonukleasy MeSH
• luteolin MeSH
• virové proteiny MeSH