Evolutionary constraints on chaperone-mediated folding provide an antiviral approach refractory to development of drug resistance
Evolutionary constraints on chaperone-mediated folding provide an antiviral approach refractory to development of drug resistance
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DOI：
10.1101/gad.1505307
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发表时间：
2007-01-15
影响因子：
10.5
通讯作者：
Frydman, Judith
中科院分区：
文献类型：
--
作者：
Geller, Ron;Vignuzzi, Marco;Frydman, Judith
RNA病毒的基因组多样性使其能够快速适应各种不利条件。因此，病毒可以逃脱大多数针对病毒或宿主因素的抗病毒化合物的抑制。在这里，我们利用RNA病毒的快速适应能力来探索伴侣蛋白介导的蛋白质折叠的进化限制。我们假设，抑制病毒蛋白质折叠所需的宿主分子伴侣将迫使病毒进化出另一种折叠策略。我们发现Hsp90是小核糖核酸病毒衣壳蛋白折叠和成熟所必需的因子。药物抑制Hsp90可抑制脊髓灰质炎病毒、鼻病毒和柯萨奇病毒在细胞培养中的复制。引人注目的是，抗Hsp90的治疗没有产生抗药性病毒，这表明衣壳折叠的复杂性排除了替代折叠途径的出现。这些结果揭示了对伴侣介导的蛋白质折叠的严格进化限制，这可能被利用来在体内抑制病毒。事实上，Hsp90抑制剂大大减少了受感染动物中脊髓灰质炎病毒的复制，而没有出现耐药逃逸突变。我们认为，病毒蛋白的靶向折叠可能提供一种一般的抗病毒策略，而这种策略对耐药性的发展是困难的。
The genome diversity of RNA viruses allows for rapid adaptation to a wide variety of adverse conditions. Accordingly, viruses can escape inhibition by most antiviral compounds targeting either viral or host factors. Here we exploited the capacity of RNA viruses for rapid adaptation to explore the evolutionary constraints of chaperone-mediated protein folding. We hypothesized that inhibiting a host molecular chaperone required for folding of a viral protein would force the virus to evolve an alternate folding strategy. We identified the chaperone Hsp90 as an essential factor for folding and maturation of picornavirus capsid proteins. Pharmacological inhibition of Hsp90 impaired the replication of poliovirus, rhinovirus, and coxsackievirus in cell culture. Strikingly, anti-Hsp90 treatment did not yield drug-resistant viruses, suggesting that the complexity of capsid folding precludes the emergence of alternate folding pathways. These results reveal tight evolutionary constraints on chaperone-mediated protein folding, which may be exploited for viral inhibition in vivo. Indeed, Hsp90 inhibitors drastically reduced poliovirus replication in infected animals without the emergence of drug-resistant escape mutants. We propose that targeting folding of viral proteins may provide a general antiviral strategy that is refractory to development of drug resistance.