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.

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  • Author(s): August EM;August EM; Qian HY; Birks EM; Thombre UA; Lin TS; Prusoff WH
  • Source:
    Biochemical pharmacology [Biochem Pharmacol] 1993 Jan 07; Vol. 45 (1), pp. 223-30.
  • Publication Type:
    Comparative Study; Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: Elsevier Science Country of Publication: England NLM ID: 0101032 Publication Model: Print Cited Medium: Print ISSN: 0006-2952 (Print) Linking ISSN: 00062952 NLM ISO Abbreviation: Biochem Pharmacol Subsets: MEDLINE
    • Publication Information:
      Publication: Oxford : Elsevier Science
      Original Publication: Oxford, New York [etc.] Paragamon Press.
    • Subject Terms:
      Antiviral Agents/*metabolism ; Deoxyuridine/*analogs & derivatives ; HIV-1/*drug effects ; Idoxuridine/*analogs & derivatives ; Virus Replication/*drug effects; Antiviral Agents/pharmacology ; Cell Division/drug effects ; Cell Line/drug effects ; DNA/biosynthesis ; DNA Polymerase II/antagonists & inhibitors ; Deoxyuridine/metabolism ; Deoxyuridine/pharmacology ; HIV Reverse Transcriptase ; Humans ; Idoxuridine/metabolism ; Idoxuridine/pharmacology ; Kinetics ; Nucleoside-Phosphate Kinase/antagonists & inhibitors ; Phosphorylation ; Protein Biosynthesis ; RNA/biosynthesis ; Reverse Transcriptase Inhibitors ; Thymidine Kinase/antagonists & inhibitors
    • Abstract:
      3'-Azido-2',3'-dideoxy-5-iodouridine (AzIdUrd) and 3'-azido-2',3'-dideoxy-5-bromouridine (AzBdUrd), previously shown to be potent and selective inhibitors of human immunodeficiency virus replication in vitro were minimally toxic to the uninfected human lymphoid cell line H9 (IC50 = 197 and 590 microM, respectively). Both compounds strongly inhibited the incorporation of [3H]thymidine but not [3H]deoxyadenosine into DNA, and we observed no significant inhibition of [3H]uridine incorporation into RNA or [3H]amino acid incorporation into protein. Exposure of H9 cells to AzIdUrd or AzBdUrd (100 microM, 24 hr) and pulse-labeling with [3H]thymidine resulted in approximately 80% reduction in levels of tritiated dTMP, dTDP, and dTTP relative to control. [125I]AzIdUrd was phosphorylated rapidly in H9 cells with the monophosphate accounting for over 90% of total soluble radioactivity. A relatively low but stable level of AzIdUTP was maintained over a 12-hr period. [125I]AzIdUrd was phosphorylated by a cell free extract of H9 cells at a rate approximately three times that of thymidine and its phosphorylation was inhibited by excess thymidine. AzIdUrd was found to be a competitive inhibitor of cytosolic thymidine kinase with a Ki of 2.63 microM and AzIdUMP a weak competitive inhibitor of thymidylate kinase with a Ki of 55.3 microM. Both AzIdUTP and AzBdUTP were potent competitive inhibitors of HIV-1 reverse transcriptase (Ki = 0.028 and 0.043 microM, respectively) and relatively poor inhibitors of H9 cell DNA polymerase alpha (Ki = 42.0 and 42.7 microM, respectively). Thus, 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.
    • Grant Information:
      AI-26055 United States AI NIAID NIH HHS; CA-05262 United States CA NCI NIH HHS
    • Accession Number:
      0 (Antiviral Agents)
      0 (Reverse Transcriptase Inhibitors)
      105784-82-5 (3'-azido-2',3'-dideoxy-5-bromouridine)
      63231-63-0 (RNA)
      85236-92-6 (3'-azido-2',3'-dideoxy-5-iodouridine)
      9007-49-2 (DNA)
      EC 2.7.1.21 (Thymidine Kinase)
      EC 2.7.4.4 (Nucleoside-Phosphate Kinase)
      EC 2.7.4.9 (dTMP kinase)
      EC 2.7.7.49 (HIV Reverse Transcriptase)
      EC 2.7.7.7 (DNA Polymerase II)
      LGP81V5245 (Idoxuridine)
      W78I7AY22C (Deoxyuridine)
    • Publication Date:
      Date Created: 19930107 Date Completed: 19930223 Latest Revision: 20201209
    • Publication Date:
      20221213
    • Accession Number:
      10.1016/0006-2952(93)90396-e
    • Accession Number:
      7678740