RESUMO
During the course of our screening for natural products from fungi, extracts of several cultures were found to make a family of related resorcylic acid lactone compounds, which are potent inhibitors of MEK kinase. Comparative and empirical studies of fermentation conditions improved the titers of the compounds of interest. Striking changes in the ratios and amounts of the major and minor compounds in some cases were achieved by manipulations of media composition.
Assuntos
Inibidores Enzimáticos/metabolismo , Fermentação , Fungos/metabolismo , Lactonas/metabolismo , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Meios de CulturaAssuntos
Aciltransferases/antagonistas & inibidores , Antifúngicos/isolamento & purificação , Paecilomyces/química , Aminoácidos/química , Aminoácidos/isolamento & purificação , Aminoácidos/farmacologia , Antifúngicos/química , Antifúngicos/farmacologia , Ácidos Graxos Insaturados/química , Ácidos Graxos Insaturados/isolamento & purificação , Ácidos Graxos Insaturados/farmacologia , Fungos/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Técnicas Microbiológicas , Paecilomyces/fisiologia , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/enzimologia , Serina C-PalmitoiltransferaseRESUMO
A novel anti-influenza virus compound, flutimide, was identified in extracts of a recently identified fungal species, Delitschia confertaspora (F. Pelaez, J.D. Polishook, M. Valldosera, and J.Guarro, Mycotaxon 50:115-122, 1994). The compound, a substituted 2,6-diketopiperazine, selectively inhibited the cap-dependent transcriptase of influenza A and B viruses and had no effect on the activities of other polymerases. Similar to the 4-substituted 2,4-dioxobutanoic acids, a series of transcriptase inhibitors which we described previously (J. Tomassini, H. Selnick, M.E. Davies, M.E. Armstrong, J. Baldwin, M. Bourgeois, J.Hastings, D. Hazuda, J. Lewis, W. McClements, G. Ponticello, E. Radzilowski, G. Smith, A. Tebben, and A. Wolfe, Antimicrob. Agents Chemother. 38:2827-2837, 1994), this inhibitor, which is a natural product, affected neither the initiation nor the elongation of influenza virus mRNA synthesis, but it specifically targeted the cap-dependent endonuclease of the transcriptase. Additionally, the compound was inhibitory to the replication of influenza A and B viruses in cell culture. The selective antiviral properties of this compound further demonstrate the utility of influenza virus endonuclease as a target of antiviral agents.
Assuntos
Antivirais/farmacologia , RNA Polimerases Dirigidas por DNA/antagonistas & inibidores , Vírus da Influenza A/efeitos dos fármacos , Vírus da Influenza B/efeitos dos fármacos , Piperazinas/farmacologia , Ascomicetos/química , Células Cultivadas , RNA Polimerases Dirigidas por DNA/metabolismo , Vírus da Influenza A/enzimologia , Vírus da Influenza B/enzimologia , Piperazinas/química , Piperazinas/isolamento & purificação , Capuzes de RNA/metabolismo , RNA Viral/biossíntese , Relação Estrutura-Atividade , Transcrição Gênica/efeitos dos fármacos , Replicação Viral/efeitos dos fármacosRESUMO
gamma-Pyrone-3-acetic acid (L-741,494) is a novel metabolite produced by a culture of the fungal genus Xylaria. This substance is a water-soluble, competitive, irreversible inhibitor of Interleukin-1 beta Converting Enzyme that is inactive against papain and trypsin. It has a mol wt of 154 and an empirical formula of C7H6O4. We propose the name xylaric acid for this compound.