Jacobus D. M. Herscheid

Antireverse transcriptase activity of gliotoxin analogs.

Abstract Gliotoxin analogs, containing 1, 2, 3 or 4 sulfur atoms in their epithiodioxopiperazine moiety, were found to inhibit the RNA-directed poA polymerase (reverse transcriptase) activity associated with RNA tumor viruses [murine (Moloney) leukemia virus] and to suppress the transformation of normal mouse (MO) cells by murine (Moloney) sarcoma virus. The antireverse transcriptase activity of the gliotoxin analogs depended on the number of sulfur atoms in the epithiodioxopiperazine ring in as far as the tetra- and trisulfides proved more inhibitory than the disulfide which, in turn, proved more inhibitory than the monosulfide. Inhibition of the reverse transcriptase reaction by the gliotoxin analogs could not be attributed to chelation of Mn 2+ or Zn 2+ , the necessary cofactors, since the gliotoxin analogs retained their inhibitory effects at supra-optimal Mn 2+ and Zn 2+ concentrations. However, the ability of the gliotoxin analogs to inhibit the reverse transcriptase reaction was abolished in the presence of a large excess of reducing agensts such as dithiothreitol. It would appear, therefore, that the antireverse transcriptase activity of the gliotoxin analogs directly depends on an intact di-,tri or tetra-sulfide bridge in the epithiodioxopiperazine ring.