Dipeptide alcohol-based inhibitors of eukaryotic DNA polymerase α Original Research Article

We reported previously that a novel dipeptide alcohol, l-homoserylaminoethanol (Hse-Gly-ol), is a selective inhibitor of eukaryotic DNA polymerase ε (pol ε) [Bioorg. Med. Chem. 2004, 12, 957–962]. The discovery suggests that the dipeptide structure could be a chemical frame for a DNA polymerase inhibitor. Therefore, we chemically synthesized 27 different species of dipeptide alcohols, and tested this inhibitory capability. Compound 6 (l-aspartylaminoethanol, Asp-Gly-ol) was found to be the strongest pol α inhibitor. Compound 6 did not influence the activities of other replicative DNA polymerases such as δ and ε, and had no effect on the activities of prokaryotic DNA polymerases, nor DNA metabolic enzymes such as human immunodeficiency virus type 1 reverse transcriptase, T7 RNA polymerase and bovine deoxyribonuclease I. The inhibitory effect of compound 6 on pol α was dose-dependent, and 50% inhibition was observed at a concentration of 33.5 μM. Compound 6-induced inhibition of pol α activity was non-competitive with both the DNA template-primer and the dNTP substrate. This is the first report on a water-soluble pol α-specific inhibitor, sought for precise biochemical studies of pol α. The relationships between the structures of dipeptide alcohols and the inhibition of eukaryotic DNA polymerases are discussed.