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Antimicrobial Agents and Chemotherapy, December 2001, p. 3403-3408, Vol. 45, No. 12
Division of Epidemiology and Virology,
Department of Internal Medicine,1 and
Department of Pathology,4 University of
Virginia School of Medicine, Charlottesville, Virginia, and
Department of Virology and Molecular Biology, St. Jude
Children's Research Hospital,2 and
Department of Pathology, University of
Tennessee,3 Memphis, Tennessee
Received 1 February 2001/Returned for modification 2 May
2001/Accepted 28 August 2001
RWJ-270201 is a novel cyclopentane inhibitor of influenza A and B
virus neuraminidases (NAs). We compared the ability of RWJ-270201 to
inhibit NA activity of clinical influenza isolates and viruses with
defined resistance mutations with that of zanamivir and oseltamivir carboxylate. In NA inhibition assays with influenza A viruses, the
median 50% inhibitory concentration (IC50) of RWJ-270201
(approximately 0.34 nM) was comparable to that of oseltamivir
carboxylate (0.45 nM) but lower than that of zanamivir (0.95 nM). For
influenza B virus isolates, the IC50 of RWJ-270201 (1.36 nM) was comparable to that of zanamivir (2.7 nM) and less than that of
oseltamivir carboxylate (8.5 nM). A zanamivir-resistant variant bearing
a Glu119-to-Gly (Glu119
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.12.3403-3408.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Comparison of the Activities of Zanamivir,
Oseltamivir, and RWJ-270201 against Clinical Isolates of Influenza
Virus and Neuraminidase Inhibitor-Resistant Variants
Gly) or Glu119
Ala substitution in an NA (N2) remained susceptible to RWJ-270201 and oseltamivir carboxylate. However, a zanamivir-selected variant with an Arg292
Lys substitution in an NA (N2) showed a moderate level of resistance to RWJ-270201 (IC50 = 30 nM) and zanamivir (IC50 = 20 nM) and a high level of resistance to oseltamivir carboxylate
(IC50 > 3,000 nM). The zanamivir-resistant influenza
B virus variant bearing an Arg152
Lys substitution was resistant to
each NA inhibitor (IC50 = 100 to 750 nM). The
oseltamivir-selected variant (N1) with the His274
Tyr substitution
exhibited resistance to oseltamivir carboxylate (IC50 = 400 nM) and to RWJ-270201 (IC50 = 40 nM) but
retained full susceptibility to zanamivir (IC50 = 1.5 nM). Thus, drug-resistant variants with substitutions in framework residues 119 or 274 can retain susceptibility to other NA inhibitors, whereas replacement of functional residue 152 or 292 leads to variable
levels of cross-resistance. We conclude that RWJ-270201 is a potent
inhibitor of NAs of wild-type and some zanamivir-resistant or
oseltamivir-resistant influenza A and B virus variants.
*
Corresponding author. Mailing address: Department of
Internal Medicine, Division of Epidemiology and Virology, University of
Virginia, P.O. Box 800473, Charlottesville, VA 22908. Phone: (804)
243-2705. Fax: (804) 982-0384. E-mail: lvg9b{at}virginia.edu.
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