Inhibition of activities of DNA polymerase α, β, γ, and reverse transcriptase of L1210 cells by phosphonoacetic acid

Abstract

Phosphonoacetic acid has been shown to suppress replication of DNA tumor viruses by inhibiting the activity of virus-induced DNA polymerase and consequently viral DNA synthesis. We now have evidence to show that phosphonoacetic acid inhibits also the cellular DNA polymerases α, β, and γ of L1210 cells as well as reverse transcriptases of two type C viruses. Particularly, the DNA polymerase α is just as senstive as the herpes virus-induced DNA polymerase. The DNA polymerases β and γ required seven times more phosphonoacetic acid for a 50% inhibition of their activities. Phosphonoacetic acid inhibited the activities of the reverse transcriptase and terminal deoxyribonucleotidyltransferase only at higher concentrations. Kinetic analysis with the DNA polymerase α showed that the compound is a non-competitive inhibitor with respect to the substrates and uncompetitive inhibitor with the activated DNA template. Studies on time course of phosphonoacetic acid inhibition revealed that the compound is inhibitory even after the initiation of DNA synthesis. Phosphonoacetic acid also inhibited cell growth as well as the type C virus production; at concentrations above 50 μg/ml, the inhibitory effect was more profound on the type C virus production than on cell growth.