Rifampicin and distamycin A as inhibitors of Rous sarcoma virus reverse transcriptase.

Abstract

THE reverse transcriptase associated with the virions of RNA tumour viruses is responsible for the synthesis of DNA chains on the RNA template, giving rise to RNA-DNA hybrid molecules (hyDNA). These DNA chains are released from the RNA template as single stranded DNA molecules (ssDNA) and serve as templates for the synthesis of double stranded DNA (dsDNA) molecules1–5. These synthetic processes are affected by actinomycin D, which inhibits the synthesis of dsDNA but stimulates the formation of hyDNA5,6. Moreover, the semisynthetic antibiotic rifampicin inhibits the synthesis of DNA molecules by the RNA tumour viral enzymes7–9. Both actinomycin D and rifampicin, which inhibit DNA synthesis at high concentrations (450 µg ml.−1 reaction mixture), were found to inhibit the transformation of cells by RNA tumour viruses10,11 and to inhibit DNA synthesis in mammalian cells12. Further, we have investigated the effect of hydrazone derivatives of rifamycin SV on Rous sarcoma virus (RSV) reverse transcriptase to determine whether the hydrazone side chain is responsible for the inhibitory effect on the synthesis of DNA molecules by the viral enzymes. The role of the side chain present in the antibiotic distamycin A in the inhibition of RSV reverse transcriptase was also studied. Distamycin A, a basic oligopeptide isolated from the cultures of Streptomyces distallicus13, was studied because of its ability to interact with double stranded and single stranded DNA molecules and to inhibit the transcription of the DNA by the DNA dependent RNA polymerase14. It was found that various derivatives of rifampicin inhibited the synthesis of RSV-DNA. Nevertheless, distamycin A was twenty times more effective in inhibiting the RSV enzymes.