Inhibition of bacteriophage-Q β ribonucleic acid polymerase by guanosine triphosphate analogues

Abstract

Sixteen compounds related to GTP were evaluated as inhibitors of bacteriophage-Q beta poly(C)-dependent poly(G) polymerase. Non-phosphorylated compounds, including guanine, guanosine and deoxyguanosine, were inactive. Phosphorylated compounds gave significant inhibition at millimolar concentrations. For nucleotides the feature important for inhibition was the 5'-phosphate chain. Four triphosphates, XTP, ITP, 7-methyl-GTP and 2'-O-methyl-GTP, gave 50% inhibition of both the poly(C)- and poly(U2,C)-dependent reactions at concentrations from 0.1 to 5 mM. XTP was 10-fold more potent an inhibitor of the reaction with poly(U2,C) as template. None of these four compounds was able to substitute for GTP as substrate to a significant extent. The most active compound, 2'-O-methyl-GTP, was a competitive inhibitor (Ki = 0.4 mM) of GTP in the poly(C)-dependent reaction.

Ribonucleosides and Rna

“…Of all RNA polymerases studied so far (95,96; L Beebe, G Kirschenheuter & W Pieken, unpublished data), 2'-O-methyl analogues, which occur naturally as a posttranscriptional modification of tRNA (98), allow, at best, marginal chain extension, but these analogues may serve as effective inhibitors of native RNA synthesis. The E. coli RNA polymerase displayed differential activity with nucleotide analogues, dependent on the 2'-modification as well as on the nucleohase (99)(100)(101)(102).…”