Phosphorylation of 3'-azido-3'-deoxythymidine and selective interaction of the 5'-triphosphate with human immunodeficiency virus reverse transcriptase.

  title={Phosphorylation of 3'-azido-3'-deoxythymidine and selective interaction of the 5'-triphosphate with human immunodeficiency virus reverse transcriptase.},
  author={Phillip A. Furman and James A. Fyfe and Marty H. St. Clair and Kent J. Weinhold and J. L. Rideout and George Andrew Freeman and Sandra Nusinoff Lehrman and Dani P. Bolognesi and Samuel E. Broder and Hiroaki Mitsuya},
  journal={Proceedings of the National Academy of Sciences of the United States of America},
  volume={83 21},
  • P. Furman, J. A. Fyfe, +7 authors H. Mitsuya
  • Published 1986
  • Biology, Medicine
  • Proceedings of the National Academy of Sciences of the United States of America
The thymidine analog 3'-azido-3'-deoxythymidine (BW A509U, azidothymidine) can inhibit human immunodeficiency virus (HIV) replication effectively in the 50-500 nM range [Mitsuya, H., Weinhold, K. J., Furman, P. A., St. Clair, M. H., Nusinoff-Lehrman, S., Gallo, R. C., Bolognesi, D., Barry, D. W. & Broder, S. (1985) Proc. Natl. Acad. Sci. USA 82, 7096-7100]. In contrast, inhibition of the growth of uninfected human fibroblasts and lymphocytes has been observed only at concentrations above 1 mM… Expand
Effects of (-)-2'-deoxy-3'-thiacytidine (3TC) 5'-triphosphate on human immunodeficiency virus reverse transcriptase and mammalian DNA polymerases alpha, beta, and gamma
Kinetic studies show that 3TC 5'-triphosphate is incorporated into newly synthesized DNA and that transcription is terminated in a manner identical to that found for ddCTP, which is consistent with the fact that inhibition of these enzymes by 3TC5'-tri phosphate is competitive with respect to dCTP. Expand
Effects of 3'-azido-3'-deoxythymidine on the deoxynucleotide triphosphate pools of cultured human cells.
The effects of 3'-azido-3'-deoxythymidine (AZT) on the deoxynucleotide pools of three human cell lines, HL-60, H-9, and K-562, were determined and the concentration of thymidine, and to a lesser extent deoxyuridine, increased in the media of treated cells. Expand
Cytotoxicity of 3'-azido-3'-deoxythymidine correlates with 3'-azidothymidine-5'-monophosphate (AZTMP) levels, whereas anti-human immunodeficiency virus (HIV) activity correlates with 3'-azidothymidine-5'-triphosphate (AZTTP) levels in cultured CEM T-lymphoblastoid cells.
The results strongly suggest that AZTMP is responsible for a major part of the growth inhibitor effects, while AZTTP mainly mediates the antiviral activity of AZT. Expand
Interaction of 3′‐Deoxythymidin‐2′‐ene Triphosphate (d4TTP) with Reverse Transcriptase from Human Immunodeficiency Virus a
3'-Deoxythymidin-2'-ene (d4T),I4 3'-deoxycytidin-2'-ene (d4C),5*6 and 3'-azido-3'deoxythymidine (AZT)' are potent and selective inhibitors of human immunodeficiency virus (HIV1) replication, and areExpand
The observed inhibitory potency of 3'-azido-3'-deoxythymidine 5'-triphosphate for HIV-1 reverse transcriptase depends on the length of the poly(rA) region of the template.
It is demonstrated that the observed Ki value for AZTTP depends on the length of the poly(rA) region following the primer in theRNA template, and the more adenosyl residues in the RNA template that are available for processive incorporation of TMP moieties, the lower is the observing Ki value. Expand
Differential antiviral activities and intracellular metabolism of 3'-azido-3'-deoxythymidine and 2',3'-dideoxyinosine in human cells.
The data show that AZT and ddI inhibited viral replication in all three cell lines and indicate differential antiviral activities of ddI and AZT in the different cells with the following rank order of drug sensitivity: MOLT4 > HT1080 > U937. Expand
Phosphorylation of 3'-azido-2',3'-dideoxyuridine and preferential inhibition of human and simian immunodeficiency virus reverse transcriptases by its 5'-triphosphate.
The different affinities of 3'-azido-2',3'-dideoxyuridine and 3'-zido-3'-deoxythymidine for the thymidine kinase and the Km values observed with these compounds as substrates may explain the difference in effects on human immunodeficiency virus type 1 replication in infected peripheral blood mononuclear cells observed when equimolar concentrations of the two compounds are compared. Expand
Effects of 3'-deoxynucleoside 5'-triphosphate concentrations on chain termination by nucleoside analogs during human immunodeficiency virus type 1 reverse transcription of minus-strand strong-stop DNA
The notion that the antiviral activities of ddNTP are dependent on both cellular dNTP pools and the state of cellular activation is confirmed. Expand
Different patterns of inhibition of avian myeloblastosis virus reverse transcriptase activity by 3'-azido-3'-deoxythymidine 5'-triphosphate and its threo isomer
Kinetic analysis of the (rA)n X (dT)12-18 (a standard template primer complex of polyriboadenylate and oligodeoxythymidylate of indicated length)-directed reaction revealed that erythro-AZT-TP was a competitive inhibitor with respect to dTTP, whereas threo-AZTs was a noncompetitive inhibitor. Expand
Metabolism and mode of selective inhibition of human immunodeficiency virus replication by 3'-azido-2',3'-dideoxy-5-iodouridine and 3'-azido-2',3'-dideoxy-5-bromouridine.
The high therapeutic index of these compounds is due to the sensitivity of the viral reverse transcriptase, coupled with the relative insensitivity of the host cell DNA polymerase alpha. Expand