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

A. Mazumder, D. Cooney, R. Agbaria, M. Gupta, Y. Pommier

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81 Scopus citations


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 μM, 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.

Original languageEnglish
Pages (from-to)5771-5775
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number13
StatePublished - 29 Jun 1994
Externally publishedYes

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