3 -Azido-3 -deoxythymidine phosphorylation

Furman PA, Fyfe JA, St. Clair MH, Weinhold K, et al. 1986. Phosphorylation of 3-azido-3 deoxythymidine and selective interaction of the 5 triphosphate with human immunodeficiency virus reverse transcriptase. Proc Natl Acad Sci USA. 83 8333-8337. 

However, equivalent potency of enzyme inhibition has been reported for the triphosphates of 3 -deoxythymidine and 3 -amino-3 -deoxythymidine despite the weak antiviral activity of the parent nucleosides (163) and (90) in vitro, both of which are poor substrates for phosphorylation [213, 214]. These observations suggest that the antiviral aetivity of 2, 3 -dideoxynucleo-sides may depend less on the relative inhibitory activities of the triphosphates against isolated RT, but rather reflects the affinity of the parent nucleosides for the cellular kinase enzymes effecting triphosphorylation. Nevertheless, other studies of RT inhibition by nucleoside triphosphates have demonstrated a defined SAR for modifications at the 3 -position [215], and it is likely that the azido substituent of AZT contributes both to the requisite substrate activity for the cellular phosphorylating enzymes, and the specificity of RT inhibition following conversion to the triphosphate. 

Nucleoside analogues are widely used as antiviral agents in the treatment in AIDS and AIDS-related complex. The only clinical agent approved in the United States for the treatment of AIDS is 3 -azido-3 -deoxythymidine (AZT) [54,55]. The molecular mechanism of action for this nucleoside includes conversion into its corresponding 5 -monophosphate by the action of cellular nucleoside kinase, followed by stepwise phosphorylation catalyzed by cellular nucleoside kinase to the corresponding 5 -triphosphate. These inhibit proviral DNA synthesis [55-57], catalyzed by HIV reverse transcriptase (RT), and incorporation to the 3 end of the growing DNA chain [55,58]. 

S. Nusinoff-Lehrman, D.P. Bolognesi, S. Broder, H. Mitsuya, D.W. Barry. Phosphorylation of 3 -Azido-3 -deoxythymidine and Selective Interaction of the 5 -Triphosphate with Human Immunodeflciency Virus Reverse Transcriptase, Proc. Natl. Acad. Sci. U.S.A. 83 8333 (1986). 

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