Inhibition of Influenza A and B Viruses by 2′-Deoxy-2′-Fluororibosides

Abstract

A series of 2′-deoxy-2′-fluororibosides were evaluated for anti-influenza activity in cell culture and in the mouse pneumonia model. Many were found to be potent inhibitors of Influenza A, in chick embryo fibroblast cells (IC50's 0.1–2.9 μM), and in reducing mouse lung virus titres (1–3 log10 units). Purine analogues proved the most effective, but their activity was an order of magnitude higher in MDCK cells. Anti-influenza activity correlated with intracellular triphosphate levels and with substrate specificity of 2′-deoxycytidine kinase. 2′-deoxy-2′-fluoroguanosine selected for further study was active against all influenza A and B strains tested, including one clinical isolate which proved extremely sensitive when assayed in human tracheal cultures. In vivo, 2′-deoxy-2′-fluoroguanosine (2′-fluorodGuo) was significantly more effective than amantadine or ribavirin in reducing mouse lung virus titre when treatment commenced after infection.

Inhibition of influenza virus transcription by 2'-deoxy-2'-fluoroguanosine

“…The compound also appears to inhibit secondary transcription, although this may be a secondary effect resulting from the inhibition of primary transcription. These findings are consistent with previous observations that intracellular 2Ј-fluorodGTP levels correlate with anti-influenza virus activity (16). The compound is phosphorylated efficiently by cellular enzymes, of which deoxycytidine kinase and GMP kinase are two enzymes capable of phosphorylating the compound to its mono-and on April 27, 2019 by guest http://aac.asm.org/ diphosphate forms, respectively.…”

“…Selectivity was shown with two important cellular enzymes, DNA polymerase ␣ and RNA polymerase II. In cellular assays a therapeutic ratio of 27 was observed with virus strain X31 in CE cells (16), which compares favorably to the therapeutic ratio of 38 seen with DNA polymerase ␣ in the present study. In particular, RNA polymerase II was examined because it has been shown that inhibitors of this enzyme can severely disrupt the replication of influenza virus (9,10).…”

“…on April 27, 2019 by guest http://aac.asm.org/ strain (strain X31) and of a partially resistant mutant (strain X31R) (16). In direct comparisons in two assays, the parent X31 RNA polymerase gave an average K i of 1.3 M, compared with an average K i of 13.15 M for X31R, which is a 10-fold reduction in the susceptibility of the enzyme from resistant virus.…”

“…The 2Ј-fluororibosides are potent inhibitors of influenza virus A and B strains in cell culture, in the mouse pneumonia model (16), and in the ferret model (6). All of the influenza virus strains examined were susceptible to 2Ј-deoxy-2Ј-fluoroguanosine (2Ј-fluorodGuo), but the level of inhibition varies with cell type and appears to be related to the levels of phosphorylation in these different cells.…”

2′-Deoxy-4′-azido Nucleoside Analogs Are Highly Potent Inhibitors of Hepatitis C Virus Replication Despite the Lack of 2′-α-Hydroxyl Groups

“…However, it has been shown that under certain circumstances the 2Ј-hydroxy group may be replaced by a fluoro moiety without major reduction of inhibitory potency against certain RNA polymerases. 2Ј-␣-FluoroNTPs showed antiviral potencies against influenza virus and were substrates for the RNA-dependent RNA polymerase of influenza virus (35,36). 2Ј-␣-Fluorocytidine was also assessed as an inhibitor of HCV replication but was a potent inhibitor of cell proliferation in the HCV replicon system (7,37).…”