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Carbonyldiphosphonate, a selective inhibitor of mammalian DNA polymerase delta

UMMS Affiliation

Graduate School of Biomedical Sciences; Department of Pharmacology; Department of Biochemistry and Molecular Pharmacology



Document Type


Medical Subject Headings

Animals; Cattle; DNA; DNA Polymerase II; DNA Polymerase III; DNA-Directed DNA Polymerase; Diphosphonates; Exonucleases; Molecular Structure; Phosphonoacetic Acid; Poly dA-dT; Templates, Genetic


Life Sciences | Medicine and Health Sciences


Twenty-three pyrophosphate analogues were screened as inhibitors of proliferating cell nuclear antigen independent DNA polymerase delta (pol delta) derived from calf thymus. Carbonyldiphosphonate (COMDP), also known as alpha-oxomethylenediphosphonate, inhibited pol delta with a potency (Ki = 1.8 microM) 20 times greater than that displayed for DNA polymerase alpha (pol alpha) derived from the same tissue. Characterization of the mechanism of inhibition of pol delta indicated that COMDP competed with the dNTP specified by the template and was not competitive with the template-primer. In the case of pol alpha, COMDP did not compete with either the dNTP or the polynucleotide substrate. COMDP inhibited the 3'----5' exonuclease activity of pol delta weakly, displaying an IC50 greater than 1 mM.

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Citation: Biochemistry. 1989 Oct 17;28(21):8270-4.

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