FEBS Letters 1994-08-29

Certain phosphoramidate derivatives of dideoxy uridine (ddU) are active against HIV and successfully by-pass thymidine kinase.

C McGuigan, P Bellevergue, H Sheeka, N Mahmood, A J Hay

Index: FEBS Lett. 351(1) , 11-4, (1994)

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Abstract

As part of our effort to deliver masked phosphates inside living cells we have discovered that certain phosphate triester derivatives of the inactive nucleoside analogue, dideoxy uridine (ddU) are inhibitors of HIV replication at microM levels. Moreover, we note that certain phosphoramidate derivatives retain their activity in thymidine kinase-deficient cells, which indicates that they do indeed act by intracellular release of the free nucleotide, and that they successfully by-pass the nucleoside kinase. The increased structural freedom in drug design which this allows may have implications for dealing with the emergence of resistance and may stimulate the discovery of improved therapeutic agents.