8PUP

Influenza A/California/07/2009(H1N1) endonuclease in complex with purpurogallin-like compound

Summary for 8PUP

• Entry DOI: 10.2210/pdb8pup/pdb
• Descriptor: Polymerase acidic protein, MANGANESE (II) ION, MAGNESIUM ION, ... (6 entities in total)
• Functional Keywords: rna-dependent rna polymerase, endonuclease inhibitor, purpurogallin, antivirals, viral protein
• Biological source: Influenza A virus (A/California/07/2009(H1N1)); More
• Total number of polymer chains: 1
• Total formula weight: 22383.48

Authors

Kotacka, T.,Radilova, K. (deposition date: 2023-07-17, release date: 2024-12-04, Last modification date: 2025-02-12)

Primary citation

Kral, M.,Kotacka, T.,Reiberger, R.,Panyrkova, G.,Radilova, K.,Osifova, Z.,Flieger, M.,Konvalinka, J.,Majer, P.,Kozisek, M.,Machara, A.
3'-Dehydroxypurpurogallin-4-Carboxamides as Influenza A Endonuclease Inhibitors: Synthesis, Structure-Activity Relationship Analysis, and Structural Characterization of Protein Complex.
Chemmedchem, 20:e202400577-e202400577, 2025

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 and Mn 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 values were determined using AlphaScreen technology, with the most potent inhibitors exhibiting IC 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.

PubMed: 39400442
DOI: 10.1002/cmdc.202400577

Experimental method

X-RAY DIFFRACTION (2 Å)