title: Dipeptide alcohol-based inhibitors of eukaryotic DNA polymerase alpha.
abstract: We reported previously that a novel dipeptide alcohol, l-homoserylaminoethanol (Hse-Gly-ol), is a selective inhibitor of eukaryotic DNA polymerase epsilon (pol epsilon) [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 alpha inhibitor. Compound 6 did not influence the activities of other replicative DNA polymerases such as delta and epsilon, 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 alpha was dose-dependent, and 50% inhibition was observed at a concentration of 33.5 microM. Compound 6-induced inhibition of pol alpha activity was non-competitive with both the DNA template-primer and the dNTP substrate. This is the first report on a water-soluble pol alpha-specific inhibitor, sought for precise biochemical studies of pol alpha. The relationships between the structures of dipeptide alcohols and the inhibition of eukaryotic DNA polymerases are discussed.
authors.affiliation: Laboratory of Food and Nutritional Sciences, Department of Nutritional Science, Kobe-Gakuin University, Nishi-ku, Kobe, Hyogo 651-2180, Japan.
authors.forename: Isoko
authors.initials: I
authors.lastname: Kuriyama
authors.forename: Naoki
authors.initials: N
authors.lastname: Asano
authors.forename: Ikuo
authors.initials: I
authors.lastname: Kato
authors.forename: Kyoko
authors.initials: K
authors.lastname: Ikeda
authors.forename: Masaharu
authors.initials: M
authors.lastname: Takemura
authors.forename: Hiromi
authors.initials: H
authors.lastname: Yoshida
authors.forename: Kengo
authors.initials: K
authors.lastname: Sakaguchi
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Mizushina
mesh_terms: D000438:Alcohols / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D002417:Cattle; D002460:Cell Line; D004247:DNA / Q000096:biosynthesis / Q000378:metabolism; D004256:DNA Polymerase I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004261:DNA Replication / Q000187:drug effects; D004151:Dipeptides / Q000737:chemistry* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D005057:Eukaryotic Cells / Q000201:enzymology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics
chemical_list: D000438:Alcohols; D004151:Dipeptides; D004791:Enzyme Inhibitors; D004247:DNA; D004256:DNA Polymerase I