SOME 6-AZA-5-SUBSTITUTED-2'-DEOXYURIDINES SHOW POTENT AND SELECTIVE-INHIBITION OF HERPES-SIMPLEX VIRUS TYPE-1 THYMIDINE KINASE

The synthesis and X-ray crystal structures of a series of 5-substitute d-6-aza-2'-deoxyuridines is reported. These nucleoside analogues inhib it the phosphorylation of thymidine by HSV-1 TK but have no effect on the corresponding human enzyme. Detailed examination of one analogue p roves it to be a competitive inhibitor of thymidine with a Ki of 0.34 mu M and is a very poor substrate. The analogues are not substrates fo r the enzyme and also do not inhibit the degradation of thymidine by t hymidine phosphorylase. Molecular modelling showed that the inhibitors fit well in the active site of HSV-1 TK, provided the conformation of the sugar moiety is the same for thymidine in the complex.