J Antibiot (Tokyo). 2019 Jan 9. doi: 10.1038/s41429-018-0134-z. [Epub ahead of print]
Flupyranochromene, a novel inhibitor of influenza virus cap-dependent endonuclease, from Penicillium sp. f28743.

Yamasaki M1, Igarashi M2, Sawa R2, Nosaka C2, Umekita M2, Hatano M2, Kimura T2, Iijima K2, Takizawa N2, Kato T3, Mizumoto K4, Nomoto A2.
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Influenza virus RNA polymerase has cap-dependent endonuclease activity that produces capped RNA fragments for priming viral mRNA synthesis. This enzymatic activity is essential for viral propagation, but it is not present in any host cellular enzyme, making it an attractive target for the development of anti-influenza drugs. Here, we isolated a novel inhibitor of cap-dependent endonuclease, named flupyranochromene, from the fermentation broth of the fungus Penicillium sp. f28743. Structural analysis revealed that this compound bears a putative pharmacophore that chelates divalent metal ion(s) present in the endonuclease active site in the PA subunit of the polymerase. Consistently, in vitro endonuclease assays showed that flupyranochromene exerts its inhibitory effects by blocking endonucleolytic cleavage by the PA subunit of viral RNA polymerase complex.

PMID: 30622294 DOI: 10.1038/s41429-018-0134-z