Inhibition of replication of avian influenza viruses by the neuraminidase inhibitor 4-guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid.
The sialidase inhibitor 4-guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid (4-guanidino-Neu5Ac2en), designed with computer assistance and knowledge of the crystal structure of influenza virus neuraminidase, has shown antiviral effects in animal models of human influenza (M. von Itzstein et al., Nature, 363, 418-423, 1993). Here we demonstrate that the compound efficiently inhibits the enzyme activity of all nine subtypes of avian influenza A neuraminidase in vitro. When administered intranasally to chickens infected with lethal viruses, high doses of the compound (1000 micrograms/kg) protected 85% of birds harboring A/Chick/Victoria/1/85 (H7N7), a fowl plague virus, but not chickens infected with other highly virulent viruses of the N1, N2, or N3 subtype. This differential inhibitory effect was also seen in a plaque reduction assay with Madin-Darby canine kidney cells (MDCK), where 4-guanidino-Neu5Ac2en was more effective against A/Chick/Vic/85 (H7N7) than A/FPV/Rostock/34 (H7N1). In contrast to the substantial plaque reduction observed in MDCK cells, the drug failed to inhibit plaque formation in chicken embryo fibroblasts infected with either A/Chick/Vic/85 or A/FPV/Rostock/34, regardless of its concentration. The different levels of drug efficacy seen in two cell systems most likely reflect the location of virus budding and release in polarized versus nonpolarized cells, as well as the compound's mode of extracellular action.
Gubareva
L V
LV
Department of Virology/Molecular Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38101, USA.
Penn
C R
CR
Webster
R G
RG
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D002642:Chick Embryo; D002645:Chickens; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005347:Fibroblasts / Q000821:virology; D006146:Guanidines; D009980:Influenza A virus / Q000187:drug effects* / Q000472:pathogenicity / Q000502:physiology; D005585:Influenza in Birds / Q000188:drug therapy; D009439:Neuraminidase / Q000037:antagonists & inhibitors*; D011714:Pyrans; D012794:Sialic Acids / Q000494:pharmacology*; D010948:Viral Plaque Assay; D014779:Virus Replication / Q000187:drug effects; D017201:Virus Shedding; D053243:Zanamivir
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D006146:Guanidines; D011714:Pyrans; D012794:Sialic Acids; D009439:Neuraminidase; D053243:Zanamivir