Acyclic/carbocyclic guanosine analogues as anti-herpesvirus agents

Citation
E. De Clercq et al., Acyclic/carbocyclic guanosine analogues as anti-herpesvirus agents, NUCLEOS NUC, 20(4-7), 2001, pp. 271-285
Citations number
45
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Biochemistry & Biophysics
Journal title
NUCLEOSIDES NUCLEOTIDES & NUCLEIC ACIDS
ISSN journal
1525-7770 → ACNP
Volume
20
Issue
4-7
Year of publication
2001
Pages
271 - 285
Database
ISI
SICI code
1525-7770(2001)20:4-7<271:AGAAAA>2.0.ZU;2-O
Abstract
Several guanosine analogues, i.e. acyclovir (and its oral prodrug valaciclo vir), penciclovir (in its oral prodrug form, famciclovir) and ganciclovir, are widely used for the treatment of herpesvirus [i.e. herpes simplex virus type 1 (HSV-1), and type 2 (HSV-2), varicella-zoster virus (VZV) and/or hu man cytomegalovirus (HCMV)] infections. In recent years, several new guanos ine analogues have been developed, including the 3-membered cyclopropylmeth yl and -methenyl derivatives (A-5021 and synguanol) and the 6-membered D- a nd L-cyclohexenyl derivatives. The activity of the acyclic/carbocyclic guan osine analogues has been determined against a wide spectrum of viruses, inc luding the HSV-1, HSV-2, VZV, HCMV, and also human herpesviruses type 6 (HH V-6), type 7 (HHV-7) and type 8 (HHV-8), and hepatitis B virus (HBV). The n ew guanosine analogues (i.e. A-5021 and D- and L-cyclohexenyl G) were found to be particularly active against those viruses (HSV-1, HSV-2, VZV) that e ncode for a specific thymidine kinase (TK), suggesting that their antiviral activity (at least partially) depends on phosphorylation by the virus-indu ced TK. Marked antiviral activity was also noted with A-5021 against HHV-6 and with D- and L-cyclohexenyl G against HCMV and HBV. The antiviral activi ty of the acyclic/carbocyclic nucleoside analogues could be markedly potent iated by mycophenolic acid, a potent inhibitor of inosine 5'-monophosphate (IMP) dehydrogenase. The new carbocyclic guanosine analogues (i.e. A-5021 a nd D- and L-cyclohexenyl G) hold great promise, not only as antiviral agent s for the treatment of herpesvirus infections, but also an antitumor agents for the combined gene therapy/chemotherapy of cancer, provided that (part of) the tumor cells have been transduced by the viral (HSV-1, VZV) TK gene.