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 µ, reduced the activities of all the above mentioned polymerases by 90% when (rA).(dT) was used as a template/primer. The dose-response curves for AMV and RMuLV polymerases primed with (rA).(dT) showed PFA to be a 1000-fold more active than PAA; the RMuLV polymerase activity was reduced to 50% after incubation with 0.7 µ-PFA and 0.7 m-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 µ-PFA, while PAA had no effect. The PFA inhibition was dependent on whether Mg or Mn 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 µ and 9 µ, respectively.


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