Lack of susceptibility of bicyclic nucleoside analogs, highly potent inhibitors of varicella-zoster virus, to the catabolic action of thymidine phosphorylase and dihydropyrimidine dehydrogenase.
The susceptibility of the bicyclic nucleoside analogs (BCNAs), highly potent and selective inhibitors of varicella-zoster virus (VZV), to the enzymes involved in nucleoside/nucleobase catabolism has been investigated in comparison with the established anti-VZV agent (E)-5-(2-bromovinyl)-2'-deoxyuridine [BVDU; brivudine (Zostex)]. Whereas human and bacterial thymidine phosphorylases (TPases) efficiently converted BVDU to its antivirally inactive free base (E)-5-(2-bromovinyl)uracil (BVU), BCNAs showed no evidence of conversion to the free base in the presence of these enzymes. The lack of substrate affinity of TPase for the BCNAs could be rationalized by computer-assisted molecular modeling of the BCNAs in the TPase active site. Moreover, in contrast with BVU, which is a potent and selective inhibitor of dihydropyrimidine dehydrogenase (DPD) (50% inhibitory concentration; 10 microM in the presence of a 25 microM concentration of the natural substrate thymine), the free base (Cf 1381; 6-octyl-2,3-dihydrofuro[2,3-d]pyrimidin-2-one) of BCNA (Cf 1368; 3-(2'-deoxy-beta-D-ribofuranosyl)-6-octyl-2,3-dihydrofuro[2,3-d]pyrimidin-2-one) and the free base Cf 2200 [6-(4-n-pentylphenyl)-2,3-dihydrofuro[2,3-d]pyrimidin-2-one] of BCNA (Cf 1743; 3-(2'-deoxy-beta-D-ribofuranosyl)-6-(4-n-pentylphenyl)-2,3-dihydrofuro[2,3-d]pyrimidin-2-one) did not inhibit the DPD-catalyzed catabolic reaction of pyrimidine bases (i.e., thymine) and pyrimidine base analogs [i.e., 5-fluorouracil (FU)] at a concentration of 250 microM. Consequently, whereas BVU caused a dramatic rise of FU levels in FU-treated mice, the BCNAs did not affect FU levels in such mice. From our data it is evident that BCNAs represent highly stable anti-VZV compounds that are not susceptible to breakdown by nucleoside/nucleobase catabolic enzymes and are not expected to interfere with cellular catabolic processes such as those involved in FU catabolism.
Balzarini
Jan
J
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium. jan.balzarini@rega.kuleuven.ac.be
Sienaert
Rebecca
R
Liekens
Sandra
S
Van Kuilenburg
André
A
Carangio
Antonella
A
Esnouf
Robert
R
De Clercq
Erik
E
McGuigan
Chris
C
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001665:Binding Sites; D001973:Bromodeoxyuridine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D001976:Bromouracil / Q000031:analogs & derivatives* / Q000494:pharmacology*; D042943:Dihydrouracil Dehydrogenase (NADP); D004347:Drug Interactions; D004926:Escherichia coli / Q000201:enzymology; D005472:Fluorouracil / Q000493:pharmacokinetics; D014645:Herpesvirus 3, Human / Q000187:drug effects*; D006574:Heterocyclic Compounds, 2-Ring / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D009705:Nucleosides / Q000494:pharmacology*; D010088:Oxidoreductases / Q000378:metabolism*; D013379:Substrate Specificity; D013939:Thymidine Phosphorylase / Q000378:metabolism*
D000998:Antiviral Agents; C446025:Cf 1368; D006574:Heterocyclic Compounds, 2-Ring; D009705:Nucleosides; C020235:brivudine; D001976:Bromouracil; C046140:5-(2-bromovinyl)uracil; D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP); D013939:Thymidine Phosphorylase; D001973:Bromodeoxyuridine; D005472:Fluorouracil