β‐Lapachone, an Inhibitor of Oncornavirus Reverse Transcriptase and Eukaryotic DNA Polymerase‐α

Abstract

β‐Lapachone is a naturally occurring compound that can be isolated from a number of tropical trees. It is shown to be a potent inhibitor of reverse transcriptase activity from both avian myeloblastosis virus and Rauscher murine leukaemia virus. In addition, it affects eukaryotic DNA‐dependent DNA polymerase‐α activity; 50% inhibition is reached in 60‐min incubation time by about 8 μM β‐lapachone. Enzyme activity is inhibited irrespective of the purity of the enzyme used or of the amount or type of template/primer or substrate present. The inhibitory effect of the drug is only observed in the presence of dithiothreitol. The primary site of action of β‐lapachone appears to be the enzyme protein, as is also borne out by the specificity of its action. Eukaryotic DNA‐dependent DNA polymerase‐β, prokaryotic DNA‐dependent DNA polymerase I, several other nucleic acid polymerases and some completely unrelated enzymes are not affected. Reverse transcriptase and DNA‐dependent DNA polymerase‐α may be in someway related in possessing similarly exposed ‘– SH structures’ in their active sites. β‐Lapachone thus affords a novel means of studying such interrelationships and of further characterizing enzymes.