Efficacy of 2-amino-7-(1,3-dihydroxy-2-propoxymethyl)purine for treatment of vaccinia virus (orthopoxvirus) infections in mice.
We have previously shown that the N-7 substituted acyclic nucleoside analog 2-amino-7-[1,3-dihydroxy-2-propoxy)methyl]purine (compound S2242) is, both in vitro and in animal models, a potent inhibitor of the replication of several herpesviruses (Neyts et al., Antimicrob. Agents Chemother. 39:56-60, 1995). Here we report on the potent and selective antiviral activity of S2242 against vaccinia virus (VV), an orthopoxvirus. The 50% effective concentrations for inhibition of VV-induced cytopathic effect and viral DNA synthesis in cell culture were 2.4 and 0.2 microg/ml, respectively. We next studied the efficacy of S2242 in VV-infected mice. Immunocompetent NMRI mice that had been inoculated intravenously with VV developed tail lesions. Mice that had been treated for 5 consecutive days via the subcutaneous (s.c.) route with 100 mg of the diacetate ester prodrug of S2242 (compound H961) per kg of body weight did not develop any lesions and demonstrated no adverse effects. Severe combined immunodeficient (SCID) mice that had been inoculated intraperitoneally with VV became sick and died within 1 month after infection. Following treatment with H961 at 100 mg/kg for 10 consecutive days (either via oral gavage or s.c. injection) VV-inoculated SCID mice were completely protected, for at least 3 months, against virus-induced morbidity and mortality. At that time, no virus could be recovered from the organs of these mice (as assessed by titration for infectious virus, a DNA hybridization assay, and a PCR for VV-specific sequences). Compound S2242 and its oral prodrug H961 could be useful in treatment of orthopoxvirus infections.
Neyts
J
J
Rega Institute for Medical Research, Katholieke Universiteit Leuven, 3000 Leuven, Belgium. Johan.Neyts@rega.kuleuven.ac.be
De Clercq
E
E
D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use*; D002478:Cells, Cultured; D004279:DNA, Viral / Q000096:biosynthesis; D007121:Immunocompetence; D051379:Mice; D016513:Mice, SCID; D011355:Prodrugs / Q000627:therapeutic use*; D011687:Purines / Q000627:therapeutic use*; D013623:Tail / Q000473:pathology; D014615:Vaccinia / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D014616:Vaccinia virus
D000998:Antiviral Agents; D004279:DNA, Viral; D011355:Prodrugs; D011687:Purines; C092709:S 2242