SUMMARYAntiviral drugs have traditionally been developed by directly targeting essential viral components. However, this strategy often fails due to the rapid generation of drug-resistant viruses. Recent genome-wide approaches, such as those employing small interfering RNA (siRNA) or clustered regularly interspaced short palindromic repeats (CRISPR) or those using small molecule chemical inhibitors targeting the cellular "kinome," have been used successfully to identify cellular factors that can support virus replication. Since some of these cellular factors are critical for virus replication, but are dispensable for the host, they can serve as novel targets for antiviral drug development. In addition, potentiation of immune responses, regulation of cytokine storms, and modulation of epigenetic changes upon virus infections are also feasible approaches to control infections. Because it is less likely that viruses will mutate to replace missing cellular functions, the chance of generating drug-resistant mutants with host-targeted inhibitor approaches is minimized. However, drug resistance against some host-directed agents can, in fact, occur under certain circumstances, such as long-term selection pressure of a host-directed antiviral agent that can allow the virus the opportunity to adapt to use an alternate host factor or to alter its affinity toward the target that confers resistance. This review describes novel approaches for antiviral drug development with a focus on host-directed therapies and the potential mechanisms that may account for the acquisition of antiviral drug resistance against host-directed agents.

中文翻译：

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宿主指导的抗病毒治疗。

发明内容传统上，抗病毒药物是通过直接靶向必需的病毒成分而开发的。但是，由于耐药病毒的快速产生，该策略通常会失败。最近的全基因组方法，例如采用小干扰RNA（siRNA）或成簇规则间隔的短回文重复序列（CRISPR）的方法，或使用针对细胞“激酶”的小分子化学抑制剂的方法，已成功用于鉴定可支持病毒复制。由于这些细胞因子中的某些对于病毒复制至关重要，但对于宿主而言却是必不可少的，因此它们可以作为抗病毒药物开发的新靶标。此外，增强免疫反应，调节细胞因子风暴，对病毒感染进行表观遗传改变和调节也是控制感染的可行方法。由于病毒发生突变以替换缺失的细胞功能的可能性较小，因此使用针对宿主的抑制剂方法产生抗药性突变体的机会得以最小化。但是，实际上，在某些情况下可能会出现针对某些宿主导向剂的耐药性，例如宿主导向抗病毒剂的长期选择压力可能会使病毒有机会适应使用替代宿主因子或改变对目标的抵抗力。