Inhibition of human telomerase by nucleotide analogues bearing a hydrophobic group.

Abstract

Telomerase, which synthesizes telomeric DNA in eukaryotic cells, is classified as a reverse transcriptase. To clarify the susceptibility of telomerase to nucleoside 5'-triphosphates bearing a hydrophobic group on the base moiety, we studied the inhibitory effects of 2',3'-dideoxy-5-styryluridine 5'-triphosphate analogues and 9-(beta-D-arabinofuranosyl)-2-(p-n-butylanilino)purine 5'-triphosphate analogues on telomerase activity using a quantitative 'stretch PCR' assay. 2',3'-Dideoxy-5-styryluridine 5'-triphosphate (StddUTP) showed more potent inhibition than 2',3'-dideoxythymidine 5'-triphosphate (ddTTP). On the other hand, 9-(beta-D-arabinofuranosyl)-2-(p-n-butylphenyl)guanine 5'-triphosphate (BuParaGTP) showed no inhibition, even though 9-(beta-D-arabinofuranosyl)guanine 5'-triphosphate (araGTP) is a potent inhibitor of telomerase. The influence on telomerase of hydrophobic substituents on the base moieties of nucleotides is described.