Viruses co-opt host proteins to carry out their lifecycle. Repurposed host proteins may thus become functionally compromised; a situation analogous to a loss-of-function mutation. We term such host proteins viral-induced hypomorphs. Cells bearing cancer driver loss-of-function mutations have successfully been targeted with drugs perturbing proteins encoded by the synthetic lethal partners of cancer-specific mutations. Synthetic lethal interactions of viral-induced hypomorphs have the potential to be similarly targeted for the development of host-based antiviral therapeutics. Here, we use GBF1, which supports the infection of many RNA viruses, as a proof-of-concept. GBF1 becomes a hypomorph upon interaction with the poliovirus protein 3A. Screening for synthetic lethal partners of GBF1 revealed ARF1 as the top hit, disruption of which, selectively killed cells that synthesize poliovirus 3A. Thus, viral protein interactions can induce hypomorphs that render host cells vulnerable to perturbations that leave uninfected cells intact. Exploiting viral-induced vulnerabilities could lead to broad-spectrum antivirals for many viruses, including SARS-CoV-2.

中文翻译：

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GBF1的病毒蛋白参与通过合成杀伤力诱导宿主细胞脆弱性

病毒选择宿主蛋白来执行它们的生命周期。因此，重新利用的宿主蛋白可能会在功能上受到损害；类似于功能丧失突变的情况。我们将此类宿主蛋白称为病毒诱导的亚型。带有癌症驱动功能丧失突变的细胞已成功地被靶向药物，这些药物扰乱了由癌症特异性突变的合成致死伴侣编码的蛋白质。病毒诱导的亚型的合成致死相互作用有可能成为基于宿主的抗病毒疗法开发的类似目标。在这里，我们使用支持许多 RNA 病毒感染的 GBF1 作为概念验证。GBF1 在与脊髓灰质炎病毒蛋白 3A 相互作用后变成亚型。筛选 GBF1 的合成致命伙伴显示 ARF1 是最热门的，其中的中断，选择性杀死合成脊髓灰质炎病毒 3A 的细胞。因此，病毒蛋白相互作用可以诱导使宿主细胞易受扰动的亚型，从而使未感染的细胞保持完整。利用病毒引起的漏洞可能会导致许多病毒的广谱抗病毒药物，包括 SARS-CoV-2。