亲环蛋白抑制剂作为严重急性呼吸综合征冠状病毒2潜在治疗方法的计算机模拟评估
In Silico Evaluation of Cyclophilin Inhibitors as Potential Treatment for SARS-CoV-2.
作者信息
Laurie Kyle, Holcomb David, Kames Jacob, Komar Anton A, DiCuccio Michael, Ibla Juan C, Kimchi-Sarfaty Chava
机构信息
Center for Biologics Evaluation and Research, Office of Tissues and Advanced Therapies, Division of Plasma Protein Therapeutics, Food and Drug Administration, Silver Spring, Maryland, USA.
Center for Gene Regulation in Health and Disease, Department of Biological, Geological and Environmental Sciences, Cleveland State University, Cleveland, Ohio, USA.
出版信息
Open Forum Infect Dis. 2021 Apr 14;8(6):ofab189. doi: 10.1093/ofid/ofab189. eCollection 2021 Jun.
BACKGROUND
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.
METHODS
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.
RESULTS
Finally, we analyzed the literature and protein-protein interactions, finding evidence that, by inhibiting CyPA, CsA may impact coagulation proteins and hemostasis.
CONCLUSIONS
Despite CsA's promising antiviral characteristics, the interactions between cyclophilins and coagulation factors emphasize risk stratification for COVID patients with thrombosis dispositions.
背景
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多种抗病毒策略以改善患者预后。研究表明，环孢素A（CsA）在体外可降低SARS-CoV-2的复制，并降低2019冠状病毒病（COVID-19）患者的死亡率。CsA与亲环蛋白结合，亲环蛋白使脯氨酸异构化，从而影响病毒蛋白活性。
方法
我们研究了多种冠状病毒蛋白质组的脯氨酸组成，以确定可能严重依赖亲环蛋白的肽基脯氨酸异构酶活性的蛋白质，发现核衣壳（N）蛋白显著依赖亲环蛋白A（CyPA）。我们对CyPA和N蛋白的相互作用进行建模，以证明N蛋白是CsA的潜在间接治疗靶点，我们认为CsA可能通过阻碍核衣壳折叠来阻止冠状病毒复制。
结果
最后，我们分析了文献和蛋白质-蛋白质相互作用，发现有证据表明，通过抑制CyPA，CsA可能会影响凝血蛋白和止血。
结论
尽管CsA具有良好的抗病毒特性，但亲环蛋白与凝血因子之间的相互作用强调了对有血栓倾向的COVID患者进行风险分层的重要性。
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