School of Life Sciences and Technology, Tongji University, China.
Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China.
Brief Bioinform. 2021 Mar 22;22(2):976-987. doi: 10.1093/bib/bbaa341.
Emerging viral infections seriously threaten human health globally. Several challenges exist in identifying effective compounds against viral infections: (1) at the initial stage of a new virus outbreak, little information, except for its genome information, may be available; (2) although the identified compounds may be effective, they may be toxic in vivo and (3) cytokine release syndrome (CRS) triggered by viral infections is the primary cause of mortality. Currently, an integrative tool that takes all those aspects into consideration for identifying effective compounds to prevent viral infections is absent. In this study, we developed iDMer, as an integrative and mechanism-driven response system for addressing these challenges during the sudden virus outbreaks. iDMer comprises three mechanism-driven compound identification modules, that is, a virus-host interaction-oriented module, an autophagy-oriented module and a CRS-oriented module. As a one-stop integrative platform, iDMer incorporates compound toxicity evaluation and compound combination identification for virus treatment with clear mechanisms. iDMer was successfully tested on five viruses, including the current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Our results indicated that, for all five tested viruses, compounds that were reported in the literature or experimentally validated for virus treatment were enriched at the top, demonstrating the generalized effectiveness of iDMer. Finally, we demonstrated that combinations of the individual modules successfully identified combinations of compounds effective for virus intervention with clear mechanisms.
新兴病毒感染严重威胁着全球人类健康。在鉴定针对病毒感染的有效化合物方面存在以下挑战：(1) 在新病毒爆发的初始阶段，除了其基因组信息外，可能几乎没有其他信息可用；(2) 虽然已鉴定的化合物可能有效，但它们在体内可能有毒性；(3) 病毒感染引发的细胞因子释放综合征（CRS）是导致死亡率的主要原因。目前，尚缺乏一种综合考虑所有这些方面以鉴定预防病毒感染的有效化合物的工具。在本研究中，我们开发了 iDMer，作为一种综合的、机制驱动的响应系统，用于应对突发病毒爆发期间的这些挑战。iDMer 包含三个机制驱动的化合物鉴定模块，即面向病毒-宿主相互作用的模块、自噬导向的模块和 CRS 导向的模块。作为一个一站式综合平台，iDMer 整合了化合物毒性评估和用于病毒治疗的化合物组合鉴定，具有明确的机制。iDMer 已成功应用于五种病毒，包括目前的严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2)。我们的结果表明，对于所有五种测试的病毒，文献中报道或实验验证的用于病毒治疗的化合物都富集在顶部，表明 iDMer 的普遍有效性。最后，我们证明了各个模块的组合成功地鉴定了具有明确机制的用于病毒干预的化合物组合。
