HEp-2 Cell- and Herpes Simplex Virus Type 1- Induced Deoxythymidine Kinases: Inhibition by Derivatives of 5-Trifluoromethyl-2′-Deoxyuridine

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Abstract
5-Trifluoromethyl-2′-deoxyuridine (F 3 Thd), its free base and nucleotide triphosphate derivative, along with the nucleotide monophosphate and nucleotide triphosphate of deoxythymidine (dThd), were investigated as inhibitors of HEp-2 cell deoxythymidine kinase (dTK) and herpes simplex virus type 1 (HSV-1)-induced dTK. 5-Trifluoromethyluracil did not inhibit cellular or viral dTK. F 3 dThd competitively inhibited phosphorylation of dThd by both the HEp-2 cell- and the HSV-1-induced dTK. The K mapp for dThd and the K Iapp for the alternate substrate, F 3 dThd, were 3.5 and 22.5 μM for the HEp-2 cell dTK and 63.5 and 71.0 μM for the HSV-1-induced dTK. dThd-5′-PPP at 10 μM inhibited HEp-2 cell- and HSV-1-induced dTK by 94 and 22%, respectively. In comparison, 10 μM F 3 dThD-5′-PPP inhibited HEp-2 cell- and HSV-1-induced dTK 95 and 15%, respectively. These data indicate that F 3 dThd-5′-PPP may mimic dThd-5′-PPP feedback regulation of cellular and viral dTK.