In vitro antiviral activity of poly (A-U) and ellipticines.
The role of N2-methyl-9-hydroxy-ellipticine (NMHE) and N2,N6-dimethyl-9-hydroxy-ellipticine (DMHE) in modulating the antiviral activity of poly (A-U) was examined using a human foreskin fibroblast-vesicular stomatitis virus (HSF-VSV) bioassay in which the concentration of poly (A-U) was fixed at 0.05 mM or 0.2 mM while the NMHE or DMHE concentration was varied to produce variable NMHE (or DMHE)/ribonucleotide ratios ranging from 1:16 to 2:1. Poly (A-U), NMHE and DMHE tested individually were not efficacious antiviral agents. When the poly (A-U) was combined with the NMHE or DMHE, the antiviral activity of the poly (A-U) was potentiated 16- to 20-fold a NMHE (or DMHE)/ribonucleotide ratios in the region of 1/4. Poly (A-U), NMHE and DMHE induce beta-IFN. The interferon-inducing activity of the NMHE (or DMHE)/poly (A-U) combination was equal to the sum of the interferon-inducing activity of the poly (A-U) alone and the NMHE (or DMHE) alone. The direct viral inactivation study demonstrated that NMHE, DMHE, poly (A-U) and the NMHE (or DMHE)/poly (A-U) combinations did not inactivate VSV at concentrations near the 50% viral inhibitory dose. Photomicrographs of HSF cells incubated with NMHE alone or with a NMHE/poly (A-U) combination suggest that poly (A-U) affects the subcellular distribution of the NMHE by steering the NMHE to the nucleolus. These observations suggest that modulation of a nuclear process may be responsible for the enhanced antiviral activity.
Department of Chemistry, Kent State University, OH 44242.
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Jamison
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Krabill
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Flowers
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Tsai
D000470:Alkaloids / Q000494:pharmacology*; D000998:Antiviral Agents; D002478:Cells, Cultured; D004611:Ellipticines / Q000494:pharmacology*; D005347:Fibroblasts / Q000382:microbiology / Q000648:ultrastructure; D006801:Humans; D007372:Interferons / Q000494:pharmacology; D011063:Poly A-U / Q000494:pharmacology*; D014721:Vesicular stomatitis Indiana virus / Q000187:drug effects* / Q000254:growth & development / Q000648:ultrastructure; D014775:Virus Activation / Q000187:drug effects
D000470:Alkaloids; D000998:Antiviral Agents; D004611:Ellipticines; C027767:elliptinium; D011063:Poly A-U; C053305:N(2),N(6)-dimethyl-9-hydroxyellipticinium; D007372:Interferons