Premium
Highly potent and selective inhibition of varicella‐zoster virus replication by bicyclic furo[2,3‐d]pyrimidine nucleoside analogues
Author(s) -
Clercq Erik De
Publication year - 2003
Publication title -
medicinal research reviews
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.868
H-Index - 130
eISSN - 1098-1128
pISSN - 0198-6325
DOI - 10.1002/med.10035
Subject(s) - thymidine phosphorylase , pyrimidine , thymidine , nucleoside , thymine , uracil , varicella zoster virus , thymidine kinase , nucleoside analogue , biology , dihydropyrimidine dehydrogenase , enzyme , biochemistry , chemistry , virus , virology , thymidylate synthase , cancer , dna , fluorouracil , genetics , herpes simplex virus
The bicyclic furo[2,3‐ d ]pyrimidine nucleoside analogues represent an entirely new class of fused furopyrimidine derivatives with unprecedented selectivity for varicella‐zoster virus (VZV). From extensive structure‐activity relationship (SAR) studies, the 6‐( p ‐alkylphenyl)substituted furopyrimidine derivatives Cf 1742 and Cf 1743 emerged as the most potent inhibitors of VZV replication: they were found to inhibit both laboratory VZV strains and clinical VZV isolates at subnanomolar concentrations, while not being toxic to the host cells at 100,000‐fold higher concentrations. Although the precise mechanism of action of these compounds remains to be elucidated, it is clear that for their antiviral activity they depend on phosphorylation by the VZV‐encoded thymidine kinase. The furo[2,3‐ d ]pyrimidine nucleoside analogues are not susceptible to degradation by human or bacterial thymidine phosphorylase, which may otherwise release the free aglycone. Also, the latter is not inhibitory to dihydropyrimidine dehydrogenase, an enzyme involved in the degradation of thymine, uracil, and the anticancer agent 5‐fluorouracil. Further development of the furo[2,3‐ d ]pyrimidine nucleoside analogues as new therapeutic modalities for the treatment of VZV infections (i.e., varicella and herpes zoster) seems highly justified. © 2003 Wiley Periodicals, Inc. Med Res Rev. 23, No. 3, 253–274, 2003