3'-Dehydroxypurpurogallin-4-Carboxamides as Influenza A Endonuclease Inhibitors: Synthesis, Structure-Activity Relationship Analysis, and Structural Characterization of Protein Complex
Language English Country Germany Media print-electronic
Document type Journal Article
Grant support
European Union - Next Generation EU -
LX22NPO5103
National Institute of Virology and Bacteriology
Academy of Sciences of the Czech Republic
- Keywords
- Chemical synthesis, Endonuclease, Enzyme inhibition, Influenza, Metalloenzymes,
- MeSH
- Amides * chemistry pharmacology chemical synthesis MeSH
- Antiviral Agents * chemical synthesis pharmacology chemistry MeSH
- Endonucleases * antagonists & inhibitors metabolism MeSH
- Enzyme Inhibitors * chemical synthesis chemistry pharmacology MeSH
- Crystallography, X-Ray MeSH
- Gallic Acid * chemistry pharmacology analogs & derivatives chemical synthesis MeSH
- Humans MeSH
- Molecular Structure MeSH
- Influenza A virus * enzymology drug effects MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Amides * MeSH
- Antiviral Agents * MeSH
- Endonucleases * MeSH
- Enzyme Inhibitors * MeSH
- Gallic Acid * MeSH
The influenza RNA-dependent RNA polymerase harbours an endonuclease subunit characterized by a catalytic site housing two divalent metal ions. By effectively chelating both Mg2+ and Mn2+ ions, a small-molecule inhibitor with a metal-binding pharmacophore can halt endonuclease activity. Herein, two 3'-dehydroxypurpurogallin-4-carboxamide series, namely twelve C-4' unsubstituted and twelve C-4' phenyl substituted congeners were designed and prepared to be tested as inhibitors of the metal-dependent viral enzyme. These inhibitors were accessed through the chemoenzymatic reaction of gallic acid with either pyrocatechol or phenylpyrocatechol moderated by laccase, followed by amidation. Experimental IC50 values were determined using AlphaScreen technology, with the most potent inhibitors exhibiting IC50 values around 0.35 μM. Using X-ray crystallography, we analyzed structure of the endonuclease in complex with one potent 3'-dehydroxypurpurogallin-carboxamide at 2.0 Å resolution, revealing the coordination of the compound's triad of oxygen atoms with the two metal ions in the influenza A endonuclease active site.
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