SMEE DF, SIDWELL RW, MORRISON AC, BAILEY KW, LY L, BAUM EZ, WAGAMAN PC, BANTIA S; Interscience Conference on Antimicrobial Agents and Chemotherapy.
Abstr Intersci Conf Antimicrob Agents Chemother Intersci Conf Antimicrob Agents Chemother. 2000 Sep 17-20; 40: 271.
Inst. for Antiviral Res., Logan, UT
BACKGROUND: The novel cyclopentane influenza virus neuraminidase inhibitor RWJ-270201 is a potent inhibitor of influenza A and influenza B viruses in cell culture and in infected mice. Studies were done to determine resistance development and virulence of these viruses in mice.METHODS: A mouse adapted strain of influenza A/Shangdong/09/93 (H3N2) virus was passaged in cells in the presence of the drug. After 10 passages a drug-resistant virus was isolated. This virus and the wild type (WT) virus were tested for virulence in mice along with different cell-culture prepared resistant and WT A/Singapore/1/57 (H2N2) viruses.RESULTS: The resistant A/Shangdong and A/Singapore viruses were >3,000-fold more resistant to RWJ-270201 than the WT viruses in vitro. The resistant viruses were cross resistant to the neuraminidase inhibitors zanamivir and GS4071. The resistant A/Shangdong virus differed by one amino acid in the hemagglutinin (HA) (Lys189Glu change), with no changes in the neuraminidase (NA). The A/Singapore virus had mutations in both HA and NA. The A/Shangdong virus was >50-fold less virulent to mice than WT virus, producing lower lung virus titers and reduced lung consolidation. RWJ-270201 treatment of mice infected with WT A/Shangdong virus did not lead to the recovery of drug-resistant virus from lungs. Infection of mice with resistant A/Singapore/1/57 and WT viruses showed a similar 50-fold lessening of virulence by the resistant virus.CONCLUSIONS: Resistance to RWJ-270201 is due to HA and/or NA mutation and leads to viruses exhibiting reduced virulence in mice. [Supported by contracts NO1-AI-65291 and NO1-AI-85348 from the Virology Branch, NIAID, NIH and by a grant from the R. W. Johnson Pharmaceutical Res. Inst.].KEYWORDS: Neuraminidase; Resistance; RWJ-270201
Publication Types:
Keywords:
- Animals
- Antiviral Agents
- Cyclopentanes
- In Vitro
- Influenza A virus
- Influenza B virus
- Mice
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- Muridae
- Neuraminidase
- Orthomyxoviridae
- Orthomyxoviridae Infections
- Sialic Acids
- Singapore
- Virulence
- Zanamivir
- peramivir
Other ID:
UI: 102248834
From Meeting Abstracts