Nicotinic Cholinergic System and COVID-19: In Silico Identification of an Interaction between SARS-CoV-2 and Nicotinic Receptors with Potential Therapeutic Targeting Implications
Nicotinic Cholinergic System and COVID-19: In Silico Identification of an Interaction between SARS-CoV-2 and Nicotinic Receptors with Potential Therapeutic Targeting Implications
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DOI：
10.3390/ijms21165807
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发表时间：
2020-08-01
影响因子：
5.6
通讯作者：
Poulas, Konstantinos
中科院分区：
文献类型：
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作者：
Farsalinos, Konstantinos;Eliopoulos, Elias;Poulas, Konstantinos
虽然SARS-CoV-2使用血管紧张素转换酶2 （ACE2）作为进入细胞的受体，但检查病毒与其他细胞受体之间的其他潜在相互作用很重要。基于住院COVID-19患者吸烟发生率低的临床观察，我们检测并鉴定了SARS-CoV-2棘突糖蛋白受体结合域（aa 375-390）中的一个“毒素样”氨基酸（aa）序列，该序列与神经毒素同源物NL1序列同源，NL1是已知与尼古丁乙酰胆碱受体（nAChRs）相互作用的众多蛇毒毒素之一。我们展示了这种“毒素样”序列在刺突糖蛋白上的三维结构位置，以及神经毒素同源物NL1和SARS-CoV-2刺突糖蛋白的模拟结构的叠加。我们还利用SARS-CoV-2刺突糖蛋白和nAChR α 9亚基胞外结构域的3D结构进行了计算分子建模和对接实验。我们确定了SARS-CoV-2刺突糖蛋白的aa 381-386与nAChR α 9亚基的细胞外结构域aa 189-192之间的主要相互作用，该区域形成了nAChR“毒素结合位点”的核心。其相互作用模式与α - 9 nAChR与α -虫毒之间的相互作用非常相似。在五聚体α - 7 AChR嵌合体与SARS-CoV-2刺突糖蛋白之间观察到类似的相互作用。这些发现提出了SARS-CoV-2可能与nachr相互作用的可能性，支持了尼古丁胆碱能系统失调与COVID-19病理生理有关的假设。尼古丁和其他尼古丁胆碱能激动剂可能保护nachr，因此在COVID-19患者中具有治疗价值。
While SARS-CoV-2 uses angiotensin converting enzyme 2 (ACE2) as the receptor for cell entry, it is important to examine other potential interactions between the virus and other cell receptors. Based on the clinical observation of low prevalence of smoking among hospitalized COVID-19 patients, we examined and identified a "toxin-like" amino acid (aa) sequence in the Receptor Binding Domain of the Spike Glycoprotein of SARS-CoV-2 (aa 375-390), which is homologous to a sequence of the Neurotoxin homolog NL1, one of the many snake venom toxins that are known to interact with nicotinic acetylcholine receptors (nAChRs). We present the 3D structural location of this "toxin-like" sequence on the Spike Glycoprotein and the superposition of the modelled structure of the Neurotoxin homolog NL1 and the SARS-CoV-2 Spike Glycoprotein. We also performed computational molecular modelling and docking experiments using 3D structures of the SARS-CoV-2 Spike Glycoprotein and the extracellular domain of the nAChR alpha 9 subunit. We identified a main interaction between the aa 381-386 of the SARS-CoV-2 Spike Glycoprotein and the aa 189-192 of the extracellular domain of the nAChR alpha 9 subunit, a region which forms the core of the "toxin-binding site" of the nAChRs. The mode of interaction is very similar to the interaction between the alpha 9 nAChR and alpha-bungarotoxin. A similar interaction was observed between the pentameric alpha 7 AChR chimera and SARS-CoV-2 Spike Glycoprotein. The findings raise the possibility that SARS-CoV-2 may interact with nAChRs, supporting the hypothesis of dysregulation of the nicotinic cholinergic system being implicated in the pathophysiology of COVID-19. Nicotine and other nicotinic cholinergic agonists may protect nAChRs and thus have therapeutic value in COVID-19 patients.