@article {Spadari1231, author = {S Spadari and G Ciarrocchi and F Focher and A Verri and G Maga and F Arcamone and E Iafrate and S Manzini and A Garbesi and L Tondelli}, title = {5-Iodo-2{\textquoteright}-deoxy-L-uridine and (E)-5-(2-bromovinyl)-2{\textquoteright}-deoxy-L-uridine: selective phosphorylation by herpes simplex virus type 1 thymidine kinase, antiherpetic activity, and cytotoxicity studies.}, volume = {47}, number = {6}, pages = {1231--1238}, year = {1995}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {5-Iodo-2{\textquoteright}-deoxy-L-uridine (L-IdU) and (E)-5-(2-bromovinyl)-2{\textquoteright}-deoxy-L-uridine (L-BVdU) have been prepared and found to inhibit herpes simplex virus type 1 (HSV-1) thymidine kinase (TK) with activities comparable to those of their analogs with the natural D-sugar configuration. The mechanism of inhibition is purely competitive for L-IdU (Ki = 0.24 microM) and mixed-type for L-BVdU (Ki = 0.13 microM). High performance liquid chromatographic analysis of the reaction products demonstrated that the viral enzyme phosphorylates both L-enantiomers to their corresponding monophosphates with efficiency comparable to that for D-enantiomers. Neither L-enantiomer inhibits the human cytosolic TK. In contrast to their D-enantiomers, L-IdU and L-BVdU have no effect on human thymidylate synthase, either in HeLa cells or in TK-deficient HeLa cells transformed with the HSV-1 TK gene. Both L-enantiomers (i) have no effect on HeLa cell growth, (ii) are 1000-fold less cytotoxic toward TK-deficient HeLa cells transformed with the HSV-1 TK gene than are their D-enantiomers, (iii) in contrast to their D-enantiomers, are fully resistant to hydrolysis by nucleoside phosphorylase, and, (iv) in spite of their much lower cytotoxicity, most probably due to the very low affinity of L-BVdU monophosphate and L-IdU monophosphate for thymidylate synthase, are only 1 or 2 orders of magnitude less potent than their D-enantiomers in inhibiting viral growth, with potency comparable to that of acyclovir.}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/47/6/1231}, eprint = {https://molpharm.aspetjournals.org/content/47/6/1231.full.pdf}, journal = {Molecular Pharmacology} }