Inhibition of neuraminidase inhibitor-resistant influenza virus by DAS181, a novel sialidase fusion protein.
Inhibition of neuraminidase inhibitor-resistant influenza virus by DAS181, a novel sialidase fusion protein.
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DOI：
10.1371/journal.pone.0007838
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发表时间：
2009-11-06
期刊：
影响因子：
3.7
通讯作者：
Fang F
中科院分区：
文献类型：
--
作者：
Triana-Baltzer GB;Gubareva LV;Klimov AI;Wurtman DF;Moss RB;Hedlund M;Larson JL;Belshe RB;Fang F
由于2009年H1N1季节性流感分离株的高流行率，其显示H274 Y相关的奥司他韦耐药性，因此流感治疗的抗病毒药物耐药性仍然是一个问题。此外，新型H1N1的出现增加了可能发生额外的再感染的可能性，导致耐药病毒。因此，迫切需要额外的抗病毒方法。DAS 181（Fludase®）是一种唾液酸酶融合蛋白，已被证明对大量季节性流感毒株和高致病性禽流感（HPAI）毒株（H5 N1）具有抑制活性。在此，我们检查了DAS 181对一组2009年奥司他韦耐药季节性H1N1临床分离株的体外活性。采用MDCK细胞上的空斑数减少试验，检查了DAS 181对9株2009年、2株2007年和2株2004年季节性IFV H1N1临床分离株的活性。DAS 181强烈抑制所有供试分离株。对2004年、2007年和2009年分离株的EC 50值保持恒定，表明DAS 181敏感性随时间推移无变化。正如预期的那样，所有2007年和2009年的分离株对奥司他韦耐药，这与所有这些分离株NA基因中H274 Y突变的鉴定一致。有趣的是，2007年和2009年的几个分离株也表现出对扎那米韦的敏感性降低，并观察到唾液酸结合位点附近伴随的HA突变。DAS 181可抑制对NAI耐药的IFV。因此，DAS 181可为对当前可用的抗病毒药物产生耐药性的季节性或大流行性IFV提供替代治疗选择。
Antiviral drug resistance for influenza therapies remains a concern due to the high prevalence of H1N1 2009 seasonal influenza isolates which display H274Y associated oseltamivir-resistance. Furthermore, the emergence of novel H1N1 raises the potential that additional reassortments can occur, resulting in drug resistant virus. Thus, additional antiviral approaches are urgently needed. DAS181 (Fludase®), a sialidase fusion protein, has been shown to have inhibitory activity against a large number of seasonal influenza strains and a highly pathogenic avian influenza (HPAI) strain (H5N1). Here, we examine the in vitro activity of DAS181 against a panel of 2009 oseltamivir-resistant seasonal H1N1 clinical isolates. The activity of DAS181 against nine 2009, two 2007, and two 2004 clinical isolates of seasonal IFV H1N1 was examined using plaque number reduction assay on MDCK cells. DAS181 strongly inhibited all tested isolates. EC50 values remained constant against isolates from 2004, 2007, and 2009, suggesting that there was no change in DAS181 sensitivity over time. As expected, all 2007 and 2009 isolates were resistant to oseltamivir, consistent with the identification of the H274Y mutation in the NA gene of all these isolates. Interestingly, several of the 2007 and 2009 isolates also exhibited reduced sensitivity to zanamivir, and accompanying HA mutations near the sialic acid binding site were observed. DAS181 inhibits IFV that is resistant to NAIs. Thus, DAS181 may offer an alternative therapeutic option for seasonal or pandemic IFVs that become resistant to currently available antiviral drugs.
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影响因子：
6.4
作者：
Ison, MG;Gubareva, LV;Hayden, FG
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