NDLI: Inhibition of human immunodeficiency virus type 1 integrase by 3'-azido-3'-deoxythymidylate.

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Inhibition of human immunodeficiency virus type 1 integrase by 3'-azido-3'-deoxythymidylate.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Mazumder, A. Agbaria, R. Cooney, D. Pommier, Y. Gupta, M.
Description	Author Affiliation: Mazumder A ( Laboratory of Molecular Pharmacology, National Cancer Institute, Bethesda, MD 20892.);
Abstract	The effects of 3'-azido-3'-deoxythymidine (AZT) and three of its intracellular metabolites, azido- thymidine mono-, di-, and triphosphates, on the human immunodeficiency virus type 1 integrase have been determined. AZT mono-, di-, and triphosphate have an IC50 for integration between 110 and 150 microM, whereas AZT does not inhibit the integrase. The inhibition by AZT monophosphate can be partially reversed by coincubation with either thymidine monophosphate or 2',3'-dideoxythymidine monophosphate, suggesting that either of these monophosphates can bind to the integrase but that the azido group at the 3' position could be responsible for the inhibition. Integrase inhibition is associated with reduced enzyme-DNA binding but does not appear to be competitive with respect to the DNA substrate. Inhibition of an integrase deletion mutant containing only amino acids 50-212 suggests that these nucleotides bind in the catalytic core. Concentrations up to 1 mM AZT monophosphate can accumulate in vivo, indicating that integrase inhibition may contribute to the antiviral effects of AZT. The increasing incidence of AZT-resistant virus strains may, therefore, be associated with mutations not only in the reverse transcriptase but also in the human immunodeficiency virus integrase. Finally, these observations suggest that additional strategies for antiviral drug development could be based upon nucleotide analogs as inhibitors of human immunodeficiency virus integrase.
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	13
Volume Number	91
Language	English
Publisher	National Academy of Sciences
Publisher Date	1994-07-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	DNA Nucleotidyltransferases Antagonists & Inhibitors HIV-1 Enzymology Thymine Nucleotides Pharmacology Zidovudine Analogs & Derivatives DNA Metabolism Dideoxynucleotides Genetics Integrases Kinetics Molecular Sequence Data Mutagenesis Oligodeoxyribonucleotides Chemistry Recombinant Proteins Sequence Deletion Substrate Specificity Virus Integration Comparative Study Multidisciplinary
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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