Z-isomers of 2-hydroxymethylcyclopropylidenemethyl adenine (synadenol) and guanine (synguanol) are active against ganciclovir- and foscarnet-resistant human cytomegalovirus UL97 mutants.
Emergence of drug-resistant human cytomegalovirus (HCMV) strains is a substantial problem during treatment of HCMV infections in immunocompromised patients. The Z-isomers of 2-hydroxymethylcyclopropylidenemethyl adenine (synadenol) and guanine (synguanol) were previously shown to be potent inhibitors of AD169 and Towne HCMV reference strains and postulated to share a common phosphorylation pathway with ganciclovir (GCV) possibly involving the UL97-encoded phosphotransferase. Analysis of synadenol and synguanol susceptibility of a series of HCMV isolates from immunocompromised untreated patients and from patients with treatment failure due to the emergence of GCV- and foscarnet (PFA)-resistant HCMV strains demonstrated that synadenol and synguanol are potent inhibitors of clinical HCMV isolates and are highly effective against both GCV- and PFA-resistant isolates. These results together with those showing resistance of a UL97 knock-out HCMV mutant to GCV as well as synadenol and synguanol suggest the involvement of UL97 phosphotransferase in synadenol and synguanol anabolism but with a substrate specificity different from that of GCV.
Baldanti
Fausto
F
Servizio di Virologia, IRCCS Policlinico S. Matteo, 27100 Pavia, Italy.
Sarasini
Antonella
A
Drach
John C
JC
Zemlicka
Jiri
J
Gerna
Giuseppe
G
D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology*; D003521:Cyclopropanes / Q000494:pharmacology*; D003587:Cytomegalovirus / Q000187:drug effects*; D003586:Cytomegalovirus Infections / Q000821:virology; D024882:Drug Resistance, Viral; D017245:Foscarnet / Q000494:pharmacology; D015774:Ganciclovir / Q000494:pharmacology; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D016867:Immunocompromised Host; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism
D000998:Antiviral Agents; D003521:Cyclopropanes; C116544:synadenol; C470351:synguanol; D017245:Foscarnet; D006147:Guanine; D017853:Phosphotransferases (Alcohol Group Acceptor); D000225:Adenine; D015774:Ganciclovir