靶向 CK2 介导的信号转导以损害/应对 SARS-CoV-2 感染：一种计算生物学方法。
Targeting CK2 mediated signaling to impair/tackle SARS-CoV-2 infection: a computational biology approach.
机构信息
Division of Informatics, Department of Bioinformatics, Center for Genetic Engineering and Biotechnology, Havana, Cuba.
Laboratory of Molecular Oncology, Division of Biomedical Research, Department of Pharmaceuticals, Center for Genetic Engineering and Biotechnology, Havana, Cuba.
出版信息
Mol Med. 2021 Dec 20;27(1):161. doi: 10.1186/s10020-021-00424-x.
BACKGROUND
Similarities in the hijacking mechanisms used by SARS-CoV-2 and several types of cancer, suggest the repurposing of cancer drugs to treat Covid-19. CK2 kinase antagonists have been proposed for cancer treatment. A recent study in cells infected with SARS-CoV-2 found a significant CK2 kinase activity, and the use of a CK2 inhibitor showed antiviral responses. CIGB-300, originally designed as an anticancer peptide, is an antagonist of CK2 kinase activity that binds to the CK2 phospho-acceptor sites. Recent preliminary results show the antiviral activity of CIGB-300 using a surrogate model of coronavirus. Here we present a computational biology study that provides evidence, at the molecular level, of how CIGB-300 may interfere with the SARS-CoV-2 life cycle within infected human cells.
METHODS
Sequence analyses and data from phosphorylation studies were combined to predict infection-induced molecular mechanisms that can be interfered by CIGB-300. Next, we integrated data from multi-omics studies and data focusing on the antagonistic effect on the CK2 kinase activity of CIGB-300. A combination of network and functional enrichment analyses was used.
RESULTS
Firstly, from the SARS-CoV studies, we inferred the potential incidence of CIGB-300 in SARS-CoV-2 interference on the immune response. Afterwards, from the analysis of multiple omics data, we proposed the action of CIGB-300 from the early stages of viral infections perturbing the virus hijacking of RNA splicing machinery. We also predicted the interference of CIGB-300 in virus-host interactions that are responsible for the high infectivity and the particular immune response to SARS-CoV-2 infection. Furthermore, we provided evidence of how CIGB-300 may participate in the attenuation of phenotypes related to muscle, bleeding, coagulation and respiratory disorders.
CONCLUSIONS
Our computational analysis proposes putative molecular mechanisms that support the antiviral activity of CIGB-300.
背景
SARS-CoV-2 与多种类型癌症的劫持机制相似，这表明可以重新利用癌症药物来治疗新冠病毒。CK2 激酶抑制剂已被提议用于癌症治疗。最近一项关于感染 SARS-CoV-2 的细胞的研究发现，CK2 激酶活性显著，使用 CK2 抑制剂可产生抗病毒反应。CIGB-300 最初被设计为一种抗癌肽，是 CK2 激酶活性的拮抗剂，可与 CK2 磷酸化受体结合。最近的初步结果表明，CIGB-300 在冠状病毒替代模型中具有抗病毒活性。在这里，我们进行了一项计算生物学研究，从分子水平上提供了证据，证明了 CIGB-300 如何干扰感染细胞中的 SARS-CoV-2 生命周期。
方法
将序列分析和磷酸化研究数据相结合，预测感染诱导的分子机制，CIGB-300 可能会干扰这些分子机制。接下来，我们整合了多组学研究数据和聚焦于 CIGB-300 对 CK2 激酶活性拮抗作用的数据。使用了网络和功能富集分析的组合。
结果
首先，我们从 SARS-CoV 研究中推断出 CIGB-300 在 SARS-CoV-2 干扰免疫反应中的潜在作用。随后，我们从多个组学数据分析中提出，CIGB-300 在病毒感染的早期阶段作用于病毒劫持 RNA 剪接机制。我们还预测了 CIGB-300 对病毒-宿主相互作用的干扰，这些相互作用负责 SARS-CoV-2 感染的高传染性和对 SARS-CoV-2 感染的特殊免疫反应。此外，我们提供了证据表明 CIGB-300 如何参与与肌肉、出血、凝血和呼吸障碍相关的表型的衰减。
结论
我们的计算分析提出了支持 CIGB-300 抗病毒活性的假定分子机制。
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