title: Acyclic/carbocyclic guanosine analogues as anti-herpesvirus agents.
abstract: Several guanosine analogues, i.e. acyclovir (and its oral prodrug valaciclovir), 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 human cytomegalovirus (HCMV)] infections. In recent years, several new guanosine analogues have been developed, including the 3-membered cyclopropylmethyl and -methenyl derivatives (A-5021 and synguanol) and the 6-membered D- and L-cyclohexenyl derivatives. The activity of the acyclic/carbocyclic guanosine analogues has been determined against a wide spectrum of viruses, including the HSV-1, HSV-2, VZV, HCMV, and also human herpesviruses type 6 (HHV-6), type 7 (HHV-7) and type 8 (HHV-8), and hepatitis B virus (HBV). The new 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 encode for a specific thymidine kinase (TK), suggesting that their antiviral activity (at least partially) depends on phosphorylation by the virus-induced 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 activity of the acyclic/carbocyclic nucleoside analogues could be markedly potentiated by mycophenolic acid, a potent inhibitor of inosine 5'-monophosphate (IMP) dehydrogenase. The new carbocyclic guanosine analogues (i.e. A-5021 and D- and L-cyclohexenyl G) hold great promise, not only as antiviral agents 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.
authors.affiliation: Rega Institute for Medical Research, K. U. Leuven, B-3000 Leuven, Belgium.
authors.forename: E
authors.initials: E
authors.lastname: De Clercq
authors.forename: G
authors.initials: G
authors.lastname: Andrei
authors.forename: R
authors.initials: R
authors.lastname: Snoeck
authors.forename: L
authors.initials: L
authors.lastname: De Bolle
authors.forename: L
authors.initials: L
authors.lastname: Naesens
authors.forename: B
authors.initials: B
authors.lastname: Degrève
authors.forename: J
authors.initials: J
authors.lastname: Balzarini
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: D
authors.initials: D
authors.lastname: Schols
authors.forename: P
authors.initials: P
authors.lastname: Leyssen
authors.forename: C
authors.initials: C
authors.lastname: Ying
authors.forename: J
authors.initials: J
authors.lastname: Neyts
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D006151:Guanosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006564:Herpesviridae / Q000187:drug effects*; D006801:Humans
chemical_list: D000998:Antiviral Agents; D006151:Guanosine