INHIBITION OF INFLUENZA-VIRUS REPLICATION IN MICE BY GG167 ANIDINO-2,4-DIDEOXY-2,3-DEHYDRO-N-ACETYLNEURAMINIC ACID) IS CONSISTENT WITH EXTRACELLULAR ACTIVITY OF VIRAL NEURAMINIDASE (SIALIDASE)

We demonstrate the potent antiviral activity of a novel viral neuramin idase (sialidase) inhibitor, anidino-2,4-dideoxy-2,3-dehydro-N-acetyln euraminic acid (GG167), administered by the intranasal route in compar ison with those of amantadine and ribavirin in experimental respirator y tract infections induced with influenza A and B viruses. In an exten ded study in which mice were infected (day 0) with influenza A/Singapo re/1/57 virus, with treatments given prophylactically plus twice daily over days 0 to 3 and with mice observed to day 10, we show that intra nasally administered GG167 at 0.4 and 0.01 mg/kg of body weight per do se reduced mortality, lung consolidation, and virus titers in the lung , with no virus growing back following the cessation of treatment. In other studies with influenza B/Victoria/102/85 virus in which infected mice were culled after the cessation of treatment, the calculated int ranasal dose required to reduce virus titers in the lungs of treated a nimals to 10% of that seen in untreated controls (ED(AUC10) [where AUC is area under the virus titer days curve]) was 0.085 mg/kg per dose. GG167 was inactive against influenza viruses A and B when given by the intraperitoneal or oral route (ED(AUC10), > 100 mg/kg per dose). GG16 7 was metabolically stable, with an elimination half-life of 10 min fo llowing intravenous administration. While readily bioavailable by syst emic routes, it was poorly bioavailable by the oral route. Its potent efficacy by the intranasal route but lack of efficacy by other routes, relative to those of amantadine and ribavirin, was explicable in term s of its in vitro activity, bioavailability, and pharmacokinetic prope rties and with the extracellular activity of viral sialidase.