Inhibition of HIV-associated reverse transcriptase by sugar-modified derivatives of thymidine 5'-triphosphate in comparison to cellular DNA polymerases alpha and beta.
The sugar-modified dTTP analogues 2',3'-didehydro-2',3'-dideoxy-thymidine 5'-triphosphate (ddeTTP), 2',3'-dideoxythymidine 5'-triphosphate (ddTTP), 3'-fluorothymidine 5'-triphosphate (FdTTP), and 3'-azidothymidine 5'-triphosphate (N3dTTP) are demonstrated to be very effective and selective inhibitors of the HIV-associated reverse transcriptase (HIV-RT). This conclusion is based on a comparison of the ID50 values of the compounds for the HIV-RT (ranging from 0.03 microM for ddeTTP to 0.1 microM for ddTTP) and the cellular DNA polymerase alpha (greater than 200 microM). DNA polymerase beta is partially affected by N3dTTP (ID50 = 31 microM) and by the other analogues (ID50 = 1-2.2 microM). FdTTP has proved as effective as N3dTTP (ID50 = 0.05 microM) in suppressing the HIV-RT activity. Kinetic analysis revealed for both dTTP analogues a competitive type of inhibition and the same K1 values (about 0.05 microM).
D002460:Cell Line; D002472:Cell Transformation, Viral; D004256:DNA Polymerase I / Q000378:metabolism*; D004257:DNA Polymerase II / Q000378:metabolism*; D006678:HIV / Q000201:enzymology*; D006801:Humans; D007700:Kinetics; D018894:Reverse Transcriptase Inhibitors; D013329:Structure-Activity Relationship; D013698:Templates, Genetic; D013942:Thymine Nucleotides / Q000494:pharmacology*
D018894:Reverse Transcriptase Inhibitors; D013942:Thymine Nucleotides; D004256:DNA Polymerase I; D004257:DNA Polymerase II