Carbonyldiphosphonate, a selective inhibitor of mammalian DNA polymerase .delta.

Abstract

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 .mu.M) 20 times greater than that displayed for DNA polymerase .alpha. (poly .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 .cntdot. primer. In the case of pol .alpha., COMDP did not compete with either the dNTP or the polynucleotide substrate. COMDP inhibited the 3'' .fwdarw. 5'' exonuclease activity of pol .delta. weakly, displaying in IC50 greater than 1 mM.