GG167 (4-guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid) is a potent inhibitor of influenza virus in ferrets

Abstract

GG167 (4-guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid) is a novel viral neuraminidase (sialidase) inhibitor which, following intranasal administration in ferrets, is at least 100 to 1,000 times more effective than ribavirin and amantadine against influenza A and B viruses. It retains its activity even when treatments are delayed until 24 h postinfection and has no effect on the serum antibody response to infection.Neuraminidase is primarily responsible for promoting the release of progeny virus from infected cells, and the selective neuraminidase inhibitor GG167 has been shown to inhibit the growth of a wide range of influenza A and B viruses in vitro (4, 5). When given intranasally to mice infected with influenza A and B viruses, GG167 was 100 to 1,000 times more active than amantadine or ribavirin and retained efficacy when treatments were delayed until the postinfection period (2). We now report on the efficacy of GG167 by the intranasal route against strains of influenza A and B viruses in a ferret model and the effects on efficacy of delaying treatments until the postinfection period.All reagents, medium components, MDCK cells, non-ferretadapted virus strains, and antiviral agents were obtained from sources given previously (2, 5). Ferrets (female, 0.6 to 1.2 kg) were obtained from Glaxo Wellcome Research and Development, Bury Green, Hertfordshire, United Kingdom, and were used in groups of three to six animals. Methods for inducing infection, for assessing and quantifying infection in terms of the area under the curve values (AUC) over days 1 to 9 of the nasal wash virus titers (log 10 50% tissue culture infective doses or PFU per milliliter), and for the telemetric monitoring of body temperature were as described previously (2, 4). Significant pyrexia is defined here as the elevation of body temperature to 1ЊC (or more) above the preinfection (baseline) temperature for at least 12 h within the 30-to 96-h-postinfection period. Unless stated otherwise, the standard treatment regimen used in efficacy tests involved 13 individual doses, starting with a single dose at Ϫ26 h (day Ϫ1) and continuing with doses at Ϫ2 and 5 h on the day of infection (day 0), at 22 and 30 h (day 1), and twice daily 8 h apart on days 2 to 5 inclusive. Where possible, ribavirin and amantadine were included at relevant dose levels and tested in parallel with at least one dose level of GG167 for each of the three viruses. Statistical analyses on nasal wash virus titer AUCs to compare treatment groups within experiments were conducted with analysis of variance; where only two groups were involved, comparisons were made with Duncan's multiple range test and the t test. Reduction in the incidence of significant pyrexia was analyzed with Fisher's exact test.The profiles of nasal wash virus titers and temperature responses over days 1 to 9 in 31 vehicle-dosed infected ferrets used in these studies were as described previously (4) and were similar for the three viruses at the challenge levels used. A total of 29 of the 31 ferret...

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