Kinetic analysis of the interaction between the diphosphate of ( S)-1-(3-hydroxy-2-phosphonylemthoxypropyl)cytosine, ddCTP, AZTTP, and FIAUTP with human DNA polymerases β and γ

Abstract

The inhibitory effects of the diphosphate of ( S)-1-(3-hydroxy-2-phosphonylemethoxypropyl)cytosine (HPMPCpp) toward human DNA polymerases β and γ were studied. The K i values of HPMPCpp were compared with the K i values of the triphosphates of 3′-azidothymidine (AZTTP), 2′,3′-dideoxycytidine (ddCTP) and 5-iodo-2′-flouroarabinosyluridine (FIAUTP). The K i values toward DNA polymerase β in increasing order were 1.32, 1.43, 140, and 520 μM for ddCTP, FIAUTP, AZTTP and HPMPCpp, respectively. The K i values toward DNA polymerase γ in increasing order were 0.034, 0.031, 18.3 and 299 μM for ddCTP, FIAUTP, AZTTP and HPMPCpp, respectively. Therefore, HPMPC would be expected to have less inhibitory effects on DNA repair (DNA polymerase β) and mitochondrial DNA synthesis (DNA polymerase γ) than ddC, FIAU or AZT.