Phosphonoformate inhibits reverse transcriptase.
The new antiviral substance phosphonoformate (PFA) has been tested in a cell-free system for its effect on reverse transcriptases from an avian retrovirus (avian myeloblastosis virus, AMV) and from mammalian retroviruses (Rauscher leukaemia virus, RMuLV; bovine leukaemia virus; baboon endogenous virus; simian sarcoma virus; visna virus). The observed inhibitory effect of PFA has been compared with that of a structurally related substance, phosphonoacetate (PAA). Phosphonoformate, at a concentration of 100 microM, reduced the activities of all the above mentioned polymerases by 90% when (rA)n.(dT)10 was used as a template/primer. The dose-response curves for AMV and RMuLV polymerases primed with (rA)n.(dT)10 showed PFA to be a 1000-fold more active than PAA; the RMuLV polymerase activity was reduced to 50% after incubation with 0.7 microM-PFA and 0.7 mM-PAA, respectively. There was no difference in PFA inhibition of virus-associated and purified reverse transcriptase activity. Results with various synthetic templates showed that both the RNA- and the DNA-dependent polymerase activities of reverse transcriptase were inhibited by PFA. The endogenous polymerase activity of AMV was inhibited to 50% at 100 microM-PFA, while PAA had no effect. The PFA inhibition was dependent on whether Mg2+ or Mn2+ was used as divalent cation in the assay. Phosphonoformate arrested DNA synthesis immediately after being added to the assay system. The mechanism of inhibition of the AMV polymerase was non-competitive with respect to substrate and template and the apparent inhibition constants were 16 microM and 9 microM, respectively.
D000818:Animals; D000998:Antiviral Agents; D009189:Avian Myeloblastosis Virus / Q000201:enzymology; D017245:Foscarnet; D000882:Haplorhini; D001909:Leukemia Virus, Bovine / Q000201:enzymology; D008274:Magnesium / Q000494:pharmacology; D008345:Manganese / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D010215:Papio / Q000382:microbiology; D010746:Phosphonoacetic Acid / Q000031:analogs & derivatives / Q000494:pharmacology*; D012194:RNA-Directed DNA Polymerase / Q000378:metabolism; D011925:Rauscher Virus / Q000201:enzymology; D012190:Retroviridae / Q000201:enzymology; D018894:Reverse Transcriptase Inhibitors; D012842:Sarcoma Virus, Woolly Monkey / Q000201:enzymology; D013698:Templates, Genetic; D014790:Visna-maedi virus / Q000201:enzymology
D000998:Antiviral Agents; D009943:Organophosphorus Compounds; D018894:Reverse Transcriptase Inhibitors; D017245:Foscarnet; D008345:Manganese; D012194:RNA-Directed DNA Polymerase; D008274:Magnesium; D010746:Phosphonoacetic Acid