Inhibition of reverse transcriptase activity of avian myeloblastosis virus by pyrophosphate analogues

Abstract

Several pyrophosphate analogues have been studied for their effects on avian myeloblastosis virus reverse transcriptase and on cellular DNA polymerase alpha. Examination of structure-activity relationships for these compounds revealed that two acidic groups connected by a short bridge were necessary, but not sufficient, for inhibition of the enzyme activities. Foscarnet sodium (trisodium phosphonoformate) was the most potent inhibitor of reverse transcriptase, giving non-competitive inhibition of reactions primed by (rA)n . (dT)12-18, (rC)n . (dG)12-18, (dC)n . (dG)12-18, and activated DNA. Carbonyldiphosphonate and 2-hydroxyphosphonoacetate also caused non-competitive inhibition patterns, whereas hypophosphate and imidodiphosphonate inhibited AMV reverse transcriptase in a competitive, non-linear manner. The reverse transcriptase reactions directed by (rA)n . (dT)12-18 and activated DNA were most affected by the non-competitive inhibitors. Hypophosphate and imidodiphosphonate inhibited preferentially reactions primed by (dC)n . (dG)12-18 and activated DNA. In all cases the (rC)n . (dG)12-18 directed reaction was the least affected.