In Silico Evaluation of Cyclophilin Inhibitors as Potential Treatment for SARS-CoV-2.
In Silico Evaluation of Cyclophilin Inhibitors as Potential Treatment for SARS-CoV-2.
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亲环素抑制剂作为SARS-CoV-2潜在治疗药物的Silico评价。
DOI：
10.1093/ofid/ofab189
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发表时间：
2021-06
影响因子：
4.2
通讯作者：
Kimchi-Sarfaty C
中科院分区：
文献类型：
--
作者：
Laurie K;Holcomb D;Kames J;Komar AA;DiCuccio M;Ibla JC;Kimchi-Sarfaty C
严重急性呼吸综合征冠状病毒2(SARS-CoV-2)的出现促使研究人员提出了多种抗病毒策略来改善患者的预后。研究证明，环孢素A(CsA)可减少SARS-CoV-2的体外复制，并降低冠状病毒病2019(新冠肺炎)患者的死亡率。CsA与亲环素结合，亲环素使脯氨酸异构化，从而影响病毒蛋白的活性。我们研究了不同冠状病毒蛋白质组的脯氨酸组成，以确定可能关键依赖于亲环素的肽-脯氨酸异构酶活性的蛋白质，发现核衣壳(N)蛋白显著依赖于亲环素A(CyPA)。我们模拟了CyPA和N蛋白的相互作用，以证明N蛋白是CsA潜在的间接治疗靶点，我们认为它可能通过阻止核衣壳折叠来阻止冠状病毒的复制。最后，我们分析了文献和蛋白质之间的相互作用，发现有证据表明，通过抑制CyPA，CsA可能影响凝血蛋白和止血。尽管CsA具有很有前景的抗病毒特性，但亲环素和凝血因子之间的相互作用强调了有血栓倾向的COVID患者的风险分层。
The advent of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) provoked researchers to propose multiple antiviral strategies to improve patients’ outcomes. Studies provide evidence that cyclosporine A (CsA) decreases SARS-CoV-2 replication in vitro and decreases mortality rates of coronavirus disease 2019 (COVID-19) patients. CsA binds cyclophilins, which isomerize prolines, affecting viral protein activity. We investigated the proline composition from various coronavirus proteomes to identify proteins that may critically rely on cyclophilin’s peptidyl-proline isomerase activity and found that the nucleocapsid (N) protein significantly depends on cyclophilin A (CyPA). We modeled CyPA and N protein interactions to demonstrate the N protein as a potential indirect therapeutic target of CsA, which we propose may impede coronavirus replication by obstructing nucleocapsid folding. Finally, we analyzed the literature and protein–protein interactions, finding evidence that, by inhibiting CyPA, CsA may impact coagulation proteins and hemostasis. Despite CsA’s promising antiviral characteristics, the interactions between cyclophilins and coagulation factors emphasize risk stratification for COVID patients with thrombosis dispositions.