INHIBITION OF REPLICATION OF AVIAN INFLUENZA-VIRUSES BY THE NEURAMINIDASE INHIBITOR 4-GUANIDINO-2,4-DIDEOXY-2,3-DEHYDRO-N-ACETYLNEURAMINIC ACID

被引:38
作者
GUBAREVA, LV
PENN, CR
WEBSTER, RG
机构
[1] ST JUDE CHILDRENS RES HOSP, DEPT VIROL MOLEC BIOL, MEMPHIS, TN 38101 USA
[2] UNIV TENNESSEE, DEPT PATHOL, MEMPHIS, TN 38163 USA
[3] DI IVANOVSKII INST VIROL, MOSCOW 123098, RUSSIA
[4] GLAXO RES & DEV LTD, DEPT VIROL, STEVENAGE SG1 2NY, HERTS, ENGLAND
关键词
D O I
10.1006/viro.1995.1489
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
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 mu g/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. (C) 1995 Academic Press, Inc.
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页码:323 / 330
页数:8
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