The anti-herpesvirus activity of (1'S,2'R)-9-[[1',2'-bis(hydroxymethyl)-cycloprop-1'-yl]methyl]guanine is markedly potentiated by the immunosuppressive agent mycophenolate mofetil.
Mycophenolic acid (MPA), the active form of the immunosuppressive agent mycophenolate mofetil (MMF), was found to markedly potentiate the anti-herpesvirus activity of the novel anti-herpesvirus agent A-5021, (1'S,2'R)-9-[[1',2'-bis(hydroxymethyl)cycloprop-1'-yl]methyl]guanine. For example, at a concentration of 1 microg/ml MPA, the activity of A-5021 against HSV-1, HSV-2 and TK(-) HSV-1 increased by a factor of 130, 14 and > or = 189, respectively. Exogenously added guanosine reversed this potentiating effect, suggesting that a depletion of the endogenous dGTP pools enhanced the inhibitory effect of the 5'-triphosphate metabolite of A-5021 on the viral DNA polymerase. The combined effect of A-5021 and MPA on the growth of uninfected Vero cells was additive rather than synergistic. The combination of topically applied MMF (5%) with 0.05% A-5021 (a subactive concentration) completely protected against HSV-1-induced cutaneous lesions in hairless mice, whereas therapy with either compound used alone had no protective effect. These findings may have implications for those transplant recipients that receive MMF as (part of) their immunosuppressive therapy and that develop intercurrent herpesvirus infections for which they need treatment.
Neyts
J
J
Rega Institute for Medical Research, Minderbroedersstraat 10, K.U. Leuven, B-3000, Leuven, Belgium. johan.neyts@rega.kuleuven.ac.be
De Clercq
E
E
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use; D002460:Cell Line; D002522:Chlorocebus aethiops; D003587:Cytomegalovirus / Q000187:drug effects; D003586:Cytomegalovirus Infections / Q000821:virology; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006147:Guanine / Q000031:analogs & derivatives / Q000494:pharmacology* / Q000627:therapeutic use*; D006561:Herpes Simplex / Q000188:drug therapy* / Q000821:virology; D018259:Herpesvirus 1, Human / Q000187:drug effects*; D006801:Humans; D051379:Mice; D008812:Mice, Hairless; D008826:Microbial Sensitivity Tests; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000494:pharmacology* / Q000627:therapeutic use; D014709:Vero Cells
C111645:9-((cis-1,2-bis(hydroxymethyl)cycloprop-1-yl)methyl)guanine; D000998:Antiviral Agents; D006147:Guanine; D009173:Mycophenolic Acid