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.