Synthesis and In Vitro Evaluation of C-7 and C-8 Luteolin Derivatives as Influenza Endonuclease Inhibitors
| Autor: | Martin Dračínský, Aleš Machara, Milan Kožíšek, Pavel Majer, Robert Reiberger, Jiří Brynda, Václav Zima, Kateřina Radilová, Michal Kráľ, Jan Konvalinka |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Stereochemistry
QH301-705.5 Protein subunit 01 natural sciences Antiviral Agents Catalysis Article Inorganic Chemistry 03 medical and health sciences Endonuclease chemistry.chemical_compound Viral Proteins Catalytic Domain cross-coupling Mannich reaction Moiety Physical and Theoretical Chemistry Biology (General) Luteolin Molecular Biology QD1-999 Spectroscopy Polymerase 030304 developmental biology chemistry.chemical_classification Orientin 0303 health sciences biology 010405 organic chemistry Chemistry Organic Chemistry General Medicine bio-isosterism endonuclease inhibitor Endonucleases Orthomyxoviridae In vitro 0104 chemical sciences Computer Science Applications Enzyme RNA polymerase flavonoids biology.protein influenza |
| Zdroj: | International Journal of Molecular Sciences, Vol 22, Iss 7735, p 7735 (2021) International Journal of Molecular Sciences Volume 22 Issue 14 |
| ISSN: | 1661-6596 1422-0067 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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