Comparison of the activities of zanamivir, oseltamivir, and RWJ-270201 against clinical isolates of influenza virus and neuraminidase inhibitor-resistant variants
Comparison of the activities of zanamivir, oseltamivir, and RWJ-270201 against clinical isolates of influenza virus and neuraminidase inhibitor-resistant variants
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DOI：
10.1128/aac.45.12.3403-3408.2001
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发表时间：
2001-12-01
影响因子：
4.9
通讯作者：
Hayden, FG
中科院分区：
文献类型：
--
作者：
Gubareva, LV;Webster, RG;Hayden, FG
RWJ-270201是一种新型环戊烷类流感病毒A、B型神经氨酸酶抑制剂。我们比较了RWJ-270201与扎那米韦和奥司他韦羧酸盐抑制临床流感分离株和具有确定耐药突变的病毒的NA活性的能力。在甲型流感病毒NA抑制试验中，RWJ-270201的半数抑制浓度（IC 50）（约0.34 nM）与奥司他韦羧酸盐（0.45 nM）相当，但低于扎那米韦（0.95 nM）。对于B流感病毒分离株，RWJ-270201（1.36 nM）的IC 50与扎那米韦（2.7 nM）相当，低于奥司他韦羧酸盐（8.5 nM）。在NA（N2）中携带Glu 119-to-Gly（Glu 119-> Gly）或Glu 119-> Ala取代的扎那米韦耐药变体仍然对RWJ-270201和奥司他韦羧酸盐敏感。然而，在NA（N2）中具有Arg 292-> Lys取代的扎那米韦选择性变体显示出对RWJ-270201（IC 50 = 30 nM）和扎那米韦（IC 50 = 20 nM）的中等水平的抗性，以及对奥司他韦羧酸盐的高水平抗性（IC 50> 3，000 nM）。携带Arg 152--> Lys取代的扎那米韦耐药B流感病毒变体对每种NA抑制剂具有耐药性（IC 50 = 100至750 nM）。具有His 274--> Tyr取代的奥司他韦选择性变体（N1）表现出对奥司他韦羧酸盐（IC 50 = 400 nM）和RWJ-270201（IC 50 = 40 nM）的抗性，但保留对扎那米韦的完全敏感性（IC 50 = 1.5 nM）。因此，在框架残基119或274中具有取代的耐药变体可以保留对其他NA抑制剂的敏感性，而功能残基152或292的取代导致可变水平的交叉抗性。我们得出结论，RWJ-270201是野生型和一些扎那米韦耐药或奥司他韦耐药的甲型和B型流感病毒变异体的NA的有效抑制剂。
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 --> 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.