Kinetic analysis of the interaction between the diphosphate of (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine, ddCTP, AZTTP, and FIAUTP with human DNA polymerases beta and gamma.
The inhibitory effects of the diphosphate of (S)-1-(3-hydroxy-2-phosphonylmethoxy-propyl)cytosine (HPMPCpp) toward human DNA polymerases beta and gamma were studied. The Ki values of HPMPCpp were compared with the Ki values of the triphosphates of 3'-azidothymidine (AZTTP), 2',3'-dideoxycytidine (ddCTP) and 5-iodo-2'-fluoroarabinosyluridine (FIAUTP). The Ki values toward DNA polymerase beta in increasing order were 1.32, 1.43, 140, and 520 microM for ddCTP, FIAUTP, AZTTP and HPMPCpp, respectively. The Ki values toward DNA polymerase gamma in increasing order were 0.034, 0.031, 18.3 and 299 microM for ddCTP, FIAUTP, AZTTP and HPMPCpp, respectively. Therefore, HPMPC would be expected to have less inhibitory effects on DNA repair (DNA polymerase beta) and mitochondrial DNA synthesis (DNA polymerase gamma) than ddC, FIAU or AZT.
Cherrington
J M
JM
Gilead Sciences, Inc., Foster City, CA 94404.
Allen
S J
SJ
McKee
B H
BH
Chen
M S
MS
D000998:Antiviral Agents / Q000494:pharmacology*; D001086:Arabinofuranosyluracil / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077404:Cidofovir; D003596:Cytosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004256:DNA Polymerase I / Q000037:antagonists & inhibitors; D004258:DNA Polymerase III / Q000037:antagonists & inhibitors; D054306:Dideoxynucleotides; D018259:Herpesvirus 1, Human / Q000201:enzymology; D018258:Herpesvirus 2, Human / Q000201:enzymology; D006801:Humans; D007700:Kinetics; D019384:Nucleic Acid Synthesis Inhibitors; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D013942:Thymine Nucleotides / Q000494:pharmacology*; D016047:Zalcitabine / Q000494:pharmacology*; D015215:Zidovudine / Q000031:analogs & derivatives* / Q000494:pharmacology
C090682:5-iodo-2'-fluoroarabinosyluridine triphosphate; D000998:Antiviral Agents; D054306:Dideoxynucleotides; D019384:Nucleic Acid Synthesis Inhibitors; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D013942:Thymine Nucleotides; D001086:Arabinofuranosyluracil; D015215:Zidovudine; D016047:Zalcitabine; C052873:zidovudine triphosphate; D003596:Cytosine; D004256:DNA Polymerase I; D004258:DNA Polymerase III; D000077404:Cidofovir