Inhibition of influenza virus replication in mice by GG167 (4-guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid) is consistent with extracellular activity of viral neuraminidase (sialidase)

Abstract

We demonstrate the potent antiviral activity of a novel viral neuraminidase (sialidase) inhibitor, 4-guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid (GG167), administered by the intranasal route in comparison with those of amantadine and ribavirin in experimental respiratory tract infections induced with influenza A and B viruses. In an extended study in which mice were infected (day 0) with influenza A/Singapore/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 intranasally administered GG167 at 0.4 and 0.01 mg/kg of body weight per dose 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 intranasal dose required to reduce virus titers in the lungs of treated animals to 10% of that seen in untreated controls (EDAUC,o [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 (EDAUC,0, >100 mg/kg per dose). GG167 was metabolically stable, with an elimination half-life of 10 min following intravenous administration. While readily bioavailable by systemic 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 terms of its in vitro activity, bioavailability, and pharmacokinetic properties and with the extracellular activity of viral sialidase.

Zanamivir: from drug design to the clinic

“…Zanamivir is readily bioavailable after intravenous, intraperitoneal and intranasal but not oral administration in mice (Ryan et al 1994). The elimination half-life (t 1/2 ) in mice after intravenous administration is ca.…”

“…No virus growth was observed in the lung homogenates after therapy was stopped. The administration of zanamivir via the oral or intraperitoneal route did not result in antiviral activity (Ryan et al 1994).…”

“…The in vivo activity of zanamivir against experimental in£uenza A and B (A/Singapore/1/57; B/Victoria/102/85) infections was examined in animal models (Ryan et al 1994). Intranasal zanamivir treatment (0.01 or 0.4 mg kg 71 per dose) given prophylactically plus twice daily over days 0 (day of viral inoculation) to 3 in mice infected with in£uenza A reduced mortality and viral titres in lung homogenates and improved lung consolidation scores over 10 days.…”

Efficacy and Safety of the Neuraminidase Inhibitor Zanamivir in the Treatment of Influenzavirus Infections

“…6,7 Zanamivir inhibits a range of influenza A and B viruses in vitro. 8,9 Topically applied zanamivir is active in animal models of influenza, 3,8,10 although systemically administered drug has little antiviral activity. In adults experimentally inoculated with influenza A virus, prophylactic intranasal zanamivir was highly protective against infection and febrile illness.…”

Ácidos siálicos: da compreensão do seu envolvimento em processos biológicos ao desenvolvimento de fármacos contra o agente etiológico da gripe

“…A partir da administração oral em camundongos, o composto GS4071 (19) mostrou biodisponibilidade levemente superior (aproximadamente 5%) que o zanamivir (6) 70,71 . Já o oseltamivir (GS4104, 7), um pró-fármaco, é cerca de cinco vezes mais biodisponível por administração oral do que 19 71,72 .…”