Hsp90 inhibitors exhibit resistance-free antiviral activity against respiratory syncytial virus.
Hsp90 inhibitors exhibit resistance-free antiviral activity against respiratory syncytial virus.
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DOI：
10.1371/journal.pone.0056762
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Frydman J
中科院分区：
文献类型：
--
作者：
Geller R;Andino R;Frydman J
呼吸道合胞病毒 (RSV) 是幼儿呼吸道疾病的主要原因，在全世界范围内导致显着的发病率和死亡率。尽管其医学重要性，但目前尚无疫苗或有效的治疗干预措施。因此，迫切需要寻找新型抗病毒药物来对抗 RSV 感染。 Hsp90 是一种细胞蛋白折叠因子，已被证明在多种病毒的复制中发挥重要作用。我们在此证明 RSV 需要 Hsp90 进行复制。机制研究表明，在 RSV 感染期间抑制 Hsp90 会导致大小与 RSV L 蛋白（病毒 RNA 依赖性 RNA 聚合酶）相似的病毒蛋白降解，表明它是 Hsp90 客户蛋白。因此，Hsp90 抑制剂对永生化和原代分化的气道上皮细胞中的实验室和临床分离的 RSV 表现出抗病毒活性。有趣的是，我们发现对 Hsp90 抑制剂耐药性的出现存在很高的障碍，因为在 Hsp90 抑制条件下 RSV 的广泛生长并没有产生对这些药物敏感性降低的突变体。我们的结果表明，Hsp90 抑制剂可能为 RSV 感染的治疗提供有吸引力的抗病毒疗法，并强调伴侣抑制剂作为抗病毒药物的潜力，对耐药性的发展表现出高度障碍。
Respiratory syncytial virus (RSV) is a major cause of respiratory illness in young children, leading to significant morbidity and mortality worldwide. Despite its medical importance, no vaccine or effective therapeutic interventions are currently available. Therefore, there is a pressing need to identify novel antiviral drugs to combat RSV infections. Hsp90, a cellular protein-folding factor, has been shown to play an important role in the replication of numerous viruses. We here demonstrate that RSV requires Hsp90 for replication. Mechanistic studies reveal that inhibition of Hsp90 during RSV infection leads to the degradation of a viral protein similar in size to the RSV L protein, the viral RNA-dependent RNA polymerase, implicating it as an Hsp90 client protein. Accordingly, Hsp90 inhibitors exhibit antiviral activity against laboratory and clinical isolates of RSV in both immortalized as well as primary differentiated airway epithelial cells. Interestingly, we find a high barrier to the emergence of drug resistance to Hsp90 inhibitors, as extensive growth of RSV under conditions of Hsp90 inhibition did not yield mutants with reduced sensitivity to these drugs. Our results suggest that Hsp90 inhibitors may present attractive antiviral therapeutics for treatment of RSV infections and highlight the potential of chaperone inhibitors as antivirals exhibiting high barriers to development of drug resistance.
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影响因子：
3.7
作者：
Chase, Geoffrey;Deng, Tao;Brownlee, George
通讯作者：
Brownlee, George
DOI：
10.1038/nrmicro1890
发表时间：
2008-05
期刊：
Nature reviews. Microbiology
影响因子：
--
作者：
Miller S;Krijnse-Locker J
通讯作者：
Krijnse-Locker J
DOI：
10.4161/hv.6.6.11562
发表时间：
2010-06
期刊：
Human vaccines
影响因子：
--
作者：
Blanco JC;Boukhvalova MS;Shirey KA;Prince GA;Vogel SN
通讯作者：
Vogel SN
影响因子：
10.5
作者：
Geller, Ron;Vignuzzi, Marco;Frydman, Judith
通讯作者：
Frydman, Judith
DOI：
10.4161/cc.7.18.6701
发表时间：
2008-09-15
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
Pashtan I;Tsutsumi S;Wang S;Xu W;Neckers L
通讯作者：
Neckers L