Most antiviral agents are designed to target virus-specific proteins and mechanisms rather than the host cell proteins that are critically dysregulated following virus-mediated reprogramming of the host cell transcriptional state. To overcome these limitations, we propose that elucidation and pharmacologic targeting of host cell Master Regulator proteins--whose aberrant activities govern the reprogramed state of coronavirus-infected cells--presents unique opportunities to develop novel mechanism-based therapeutic approaches to antiviral therapy, either as monotherapy or as a complement to established treatments. Specifically, we propose that a small module of host cell Master Regulator proteins (ViroCheckpoint) is hijacked by the virus to support its efficient replication and release. Conventional methodologies are not well suited to elucidate these potentially targetable proteins. By using the VIPER network-based algorithm, we successfully interrogated 12h, 24h, and 48h signatures from Calu-3 lung adenocarcinoma cells infected with SARS-CoV, to elucidate the time-dependent reprogramming of host cells and associated Master Regulator proteins. We used the NYS CLIA-certified Darwin OncoTreat algorithm, with an existing database of RNASeq profiles following cell perturbation with 133 FDA-approved and 195 late-stage experimental compounds, to identify drugs capable of virtually abrogating the virus-induced Master Regulator signature. This approach to drug prioritization and repurposing can be trivially extended to other viral pathogens, including SARS-CoV-2, as soon as the relevant infection signature becomes available.

中文翻译：

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宿主细胞ViroCheckpoint：冠状病毒介导的被劫持细胞状态的新机制决定因素的鉴定和药理靶向。

大多数抗病毒药物的设计目标是针对病毒特异性蛋白质和机制，而不是针对病毒介导的宿主细胞转录状态重编程后严重失调的宿主细胞蛋白质。为了克服这些局限性，我们提出宿主细胞主调节蛋白的阐明和药理靶向作用（其异常活性控制冠状病毒感染细胞的重新编程状态）为开发基于新机制的抗病毒疗法提供了独特的机会，作为单一疗法或作为既定疗法的补充。具体来说，我们建议病毒劫持一小部分宿主细胞主调节蛋白（ViroCheckpoint），以支持其有效复制和释放。常规方法不太适合阐明这些潜在的可靶向蛋白质。通过使用基于VIPER网络的算法，我们成功询问了感染SARS-CoV的Calu-3肺腺癌细胞的12h，24h和48h信号，以阐明宿主细胞和相关的Master Regulator蛋白的时间依赖性重编程。我们使用NYS CLIA认证的Darwin OncoTreat算法，以及使用133种FDA批准的195种晚期实验化合物对细胞进行扰动后，使用现有的RNASeq分布图数据库，来鉴定能够实际上消除病毒诱导的Master Regulator签名的药物。一旦获得了相关的感染特征，就可以将这种对药物进行优先排序和重新调整用途的方法简单地扩展到其他病毒病原体，包括SARS-CoV-2。