Download Mendeley3'-Dehydroxypurpurogallin-4-Carboxamides as Influenza A Endonuclease Inhibitors: Synthesis, Structure-Activity Relationship Analysis, and Structural Characterization of Protein Complex.
Kral, M., Kotacka, T., Reiberger, R., Panyrkova, G., Radilova, K., Osifova, Z., Flieger, M., Konvalinka, J., Majer, P., Kozisek, M., Machara, A.(2024) ChemMedChem : e202400577-e202400577
- PubMed: 39400442
- DOI: https://doi.org/10.1002/cmdc.202400577
- Primary Citation of Related Structures:
8PUP - PubMed Abstract:
The influenza RNA-dependent RNA polymerase harbours an endonuclease subunit characterized by a catalytic site housing two divalent metal ions. By effectively chelating both Mg 2+ and Mn 2+ 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 IC 50 values were determined using AlphaScreen technology, with the most potent inhibitors exhibiting IC 50 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.
Organizational Affiliation:
Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo náměstí 542/2, Prague 6, 160 00, Czech Republic.
