CERTAIN PHOSPHORAMIDATE DERIVATIVES OF DIDEOXY URIDINE (DDU) ARE ACTIVE AGAINST HIV AND SUCCESSFULLY BYPASS THYMIDINE KINASE

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 mu M levels. Moreover, we note that certain phosph oramidate derivatives retain their activity in thymidine kinase-defici ent cells, which indicates that they do indeed act by intracellular re lease of the free nucleotide, and that they successfully by-pass the n ucleoside kinase. The increased structural freedom in drug design whic h this allows may have implications for dealing with the emergence of resistance and may stimulate the discovery of improved therapeutic age nts.