Inhibition of cellular and virus-associated nucleotide polymerases by, and anti-herpes simplex virus activity of, streptovaricin derivatives

Abstract

Fourteen streptovaricin derivatives were tested for inhibition of cellular nucleotide polymerases (deoxyribonucleic acid polymerases alpha, beta, and gamma, terminal deoxynucleotidyltransferase [TdT], and ribonucleic acid polymerase II), simian sarcoma virus deoxyribonucleic acid polymerase, and herpes simplex virus type 1-induced deoxyribonucleic acid polymerase (HSV-DP). Three compounds (strep-tovadienal C, prestreptovarone, and streptoval Fc) preferentially inhibited TdT and HSV-DP over the other enzymes. These compounds inhibited HSV-DP more potently than they inhibited TdT. Evidence indicated that the mode of inhibition of TdT and HSV-DP by streptovadienal C and prestreptovarone was by interaction with the enzymes and not with template-primer, initiator, substrates, or divalent cations required for enzyme activity. Furthermore, data suggested that these compounds bind with greater affinity to HSV-DP than to TdT. Streptovadienal C and prestreptovarone were examined for their effect on the replication of herpes simplex virus type 1 in African green monkey kidney (CV1) cells. These compounds produced 2- and 3-log drops in virus titer, respectively, at concentrations not significantly affecting cell viability. This correlated with evidence indicating a greater binding affinity of these compounds for HSV-DP over cellular nucleotide polymerases.