In silico studies on the comparative characterization of the interactions of SARS-CoV-2 spike glycoprotein with ACE-2 receptor homologs and human TLRs
In silico studies on the comparative characterization of the interactions of SARS-CoV-2 spike glycoprotein with ACE-2 receptor homologs and human TLRs
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DOI：
10.1002/jmv.25987
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发表时间：
2020-05-17
影响因子：
12.7
通讯作者：
Mukherjee, Suprabhat
中科院分区：
文献类型：
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作者：
Choudhury, Abhigyan;Mukherjee, Suprabhat
由新型冠状病毒或严重急性呼吸综合征冠状病毒2型(SARS-CoV-2)感染引起的新冠肺炎疫情近年来已成为人类面临的主要威胁。它通过全球范围内不断增加的死亡、相关的合并症和社会经济损失，不断地给人类造成巨大的损失。化疗药物/疫苗的缺乏给科学家和医生开发紧急治疗策略带来了巨大的挑战。在这方面，本研究旨在了解SARS-CoV-2的主要感染性蛋白Spike蛋白的序列差异，以及它与人类及相关动物宿主/宿主的血管紧张素转换酶-2受体(ACE2)受体的相互作用方式。此外，人类Toll样受体(TLRs)对Spike蛋白的参与也已被证明。结果表明，SARS-CoV-2的刺突糖蛋白与蝙蝠冠状病毒亲缘关系较近，与人和蝙蝠来源的ACE2受体蛋白具有较强的亲缘关系。我们还发现，细胞表面的TLRs，特别是TLR4最有可能参与识别SARS-CoV-2的分子模式以诱导炎症反应。本研究支持SARS-CoV-2来源于蝙蝠的人兽共患病来源，并揭示TLR4可能在新冠肺炎相关的病毒诱导的炎症后果中起关键作用。因此，通过设计竞争性的TLR4拮抗剂来选择性靶向TLR4与刺激性蛋白的相互作用可能为新冠肺炎的治疗开辟一条新的途径。最后，本研究有望提高我们对SARS-CoV-2免疫生物学的认识，并可能在短期内对采用Spike蛋白、ACE2或TLR引导的新冠肺炎干预策略有所帮助。
Coronavirus disease-2019 (COVID-19) outbreak due to novel coronavirus or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has come out as a major threat for mankind in recent times. It is continually taking an enormous toll on mankind by means of increasing number of deaths, associated comorbidities, and socioeconomic loss around the globe. Unavailability of chemotherapeutics/vaccine has posed tremendous challenges to scientists and doctors for developing an urgent therapeutic strategy. In this connection, the present in silico study aims to understand the sequence divergence of spike protein (the major infective protein of SARS-CoV-2), its mode of interaction with the angiotensin-converting enzyme-2 receptor (ACE2) receptor of human and related animal hosts/reservoir. Moreover, the involvement of the human Toll-like receptors (TLRs) against the spike protein has also been demonstrated. Our data indicated that the spike glycoprotein of SARS-CoV-2 is phylogenetically close to bat coronavirus and strongly binds with ACE2 receptor protein from both human and bat origin. We have also found that cell surface TLRs, especially TLR4 is most likely to be involved in recognizing molecular patterns from SARS-CoV-2 to induce inflammatory responses. The present study supported the zoonotic origin of SARS-CoV-2 from a bat and also revealed that TLR4 may have a crucial role in the virus-induced inflammatory consequences associated with COVID-19. Therefore, selective targeting of TLR4-spike protein interaction by designing competitive TLR4-antagonists could pave a new way to treat COVID-19. Finally, this study is expected to improve our understanding on the immunobiology of SARS-CoV-2 and could be useful in adopting spike protein, ACE2, or TLR-guided intervention strategy against COVID-19 shortly.