Carbonyldiphosphonate, a selective inhibitor of mammalian DNA polymerase delta.
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.
Talanian
R V
RV
Department of Pharmacology, University of Massachusetts Medical School, Worcester 01655.
Brown
N C
NC
McKenna
C E
CE
Ye
T G
TG
Levy
J N
JN
Wright
G E
GE
D000818:Animals; D002417:Cattle; D004247:DNA / Q000378:metabolism; D004257:DNA Polymerase II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004258:DNA Polymerase III / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004164:Diphosphonates / Q000494:pharmacology*; D005092:Exonucleases / Q000378:metabolism; D015394:Molecular Structure; D019384:Nucleic Acid Synthesis Inhibitors; D010746:Phosphonoacetic Acid / Q000494:pharmacology; D011067:Poly dA-dT / Q000378:metabolism; D013698:Templates, Genetic
D004164:Diphosphonates; D019384:Nucleic Acid Synthesis Inhibitors; C062324:carbonyldiphosphonate; D011067:Poly dA-dT; C027474:methylene diphosphonate; D004247:DNA; D004257:DNA Polymerase II; D004258:DNA Polymerase III; D005092:Exonucleases; D010746:Phosphonoacetic Acid