SARS-CoV-2 is a highly contagious virus that has caused serious health crisis world-wide resulting into a pandemic situation. As per the literature, the SARS-CoV-2 is known to exploit humanACE2 receptors (similar toprevious SARS-CoV-1) for gaining entry into the host cell for invasion, infection, multiplication and pathogenesis. However, considering the higher infectivity of SARS-CoV-2 along with the complex etiology and pathophysiological outcomes seen in COVID-19 patients, it seems that there may be an alternate receptor for SARS-CoV-2. I performed comparative protein sequence analysis, database based gene expression profiling, bioinformatics based molecular docking using authentic tools and techniques for unveiling the molecular basis of high infectivity of SARS-CoV-2 as compared to previous known coronaviruses. My study revealed that SARS-CoV-2 (previously known as 2019-nCoV) harbors a RGD motif in its receptor binding domain (RBD) and the motif is absent in all other previously known SARS-CoVs. The RGD motif is well known for its role in cell-attachment and cell-adhesion. My hypothesis is that the SARS-CoV-2 may be (via RGD) exploiting integrins, that have high expression in lungs and all other vital organs, for invading host cells. However, an experimental verification is required. The expression of ACE2, which is a known receptor for SARS-CoV-2, was found to be negligible in lungs. I assume that higher infectivity of SARS-CoV-2 could be due to this RGD-integrin mediated acquired cell-adhesive property. Gene expression profiling revealed that expression of integrins is significantly high in lung cells, in particular αvβ6, α5β1, αvβ8 and an ECM protein, ICAM1. The molecular docking experiment showed the RBD of spike protein binds with integrins precisely at RGD motif in a similar manner as a synthetic RGD peptide binds to integrins as found by other researchers. SARS-CoV-2 spike protein has a number of phosphorylation sites that can induce cAMP, PKC, Tyr signaling pathways. These pathways either activate calcium ion channels or get activated by calcium. In fact, integrins have calcium & metal binding sites that were predicted around and in vicinity of RGD-integrin docking site in our analysis which suggests that RGD-integrins interaction possibly occurs in calcium-dependent manner. The higher expression of integrins in lungs along with their previously known high binding affinity (~K_D = 4.0 nM) for virus RGD motif could serve as a possible explanation for high infectivity of SARS-CoV-2. On the contrary, human ACE2 has lower expression in lungs and its high binding affinity (~K_D = 15 nM) for spike RBD alone could not manifest significant virus-host attachment. This suggests that besides human ACE2, an additional or alternate receptor for SARS-CoV-2 is likely to exist. A highly relevant evidence never reported earlier which corroborate in favor of RGD-integrins mediated virus-host attachment is an unleashed cytokine storm which causes due to activation of TNF-α and IL-6 activation; and integrins role in their activation is also well established. Altogether, the current study has highlighted possible role of calcium and other divalent ions in RGD-integrins interaction for virus invasion into host cells and suggested that lowering divalent ion in lungs could avert virus-host cells attachment.

SARS-CoV-2 是一种高度传染性病毒，已在全球范围内造成严重的健康危机，导致大流行。根据文献，已知 SARS-CoV-2 利用人类 ACE2 受体（类似于以前的 SARS-CoV-1）进入宿主细胞进行入侵、感染、增殖和发病。然而，考虑到 SARS-CoV-2 的较高传染性以及在 COVID-19 患者中观察到的复杂病因学和病理生理学结果，似乎 SARS-CoV-2 可能存在替代受体。我使用真实的工具和技术进行了比较蛋白质序列分析、基于数据库的基因表达谱分析、基于生物信息学的分子对接，以揭示 SARS-CoV-2 与以前已知的冠状病毒相比具有高传染性的分子基础。我的研究表明，SARS-CoV-2（以前称为 2019-nCoV）在其受体​​结合域 (RBD) 中包含一个 RGD 基序，而该基序在所有其他先前已知的 SARS-CoV 中都不存在。RGD 基序因其在细胞附着和细胞粘附中的作用而广为人知。我的假设是 SARS-CoV-2 可能（通过 RGD）利用在肺和所有其他重要器官中高表达的整合素来入侵宿主细胞。但是，需要进行实验验证。ACE2 的表达是 SARS-CoV-2 的已知受体，被发现在肺部的表达可以忽略不计。我认为 SARS-CoV-2 较高的传染性可能是由于这种 RGD 整合素介导的获得性细胞粘附特性。基因表达谱显示整合素在肺细胞中的表达非常高，特别是 αvβ6、α5β1、αvβ8 和 ECM 蛋白，ICAM1。分子对接实验表明，刺突蛋白的 RBD 在 RGD 基序上与整合素精确结合，其方式与其他研究人员发现的合成 RGD 肽与整合素结合的方式类似。SARS-CoV-2刺突蛋白具有多个磷酸化位点，可诱导cAMP、PKC、Tyr信号通路。这些途径要么激活钙离子通道，要么被钙激活。事实上，在我们的分析中，整合素在 RGD-整合素对接位点周围和附近预测有钙和金属结合位点，这表明 RGD-整合素相互作用可能以钙依赖性方式发生。整合素在肺中的更高表达及其先前已知的高结合亲和力 (~K 分子对接实验表明，刺突蛋白的 RBD 在 RGD 基序上与整合素精确结合，其方式与其他研究人员发现的合成 RGD 肽与整合素结合的方式类似。SARS-CoV-2刺突蛋白具有多个磷酸化位点，可诱导cAMP、PKC、Tyr信号通路。这些途径要么激活钙离子通道，要么被钙激活。事实上，在我们的分析中，整合素在 RGD-整合素对接位点周围和附近预测有钙和金属结合位点，这表明 RGD-整合素相互作用可能以钙依赖性方式发生。整合素在肺中的更高表达及其先前已知的高结合亲和力 (~K 分子对接实验表明，刺突蛋白的 RBD 在 RGD 基序上与整合素精确结合，其方式与其他研究人员发现的合成 RGD 肽与整合素结合的方式类似。SARS-CoV-2刺突蛋白具有多个磷酸化位点，可诱导cAMP、PKC、Tyr信号通路。这些途径要么激活钙离子通道，要么被钙激活。事实上，在我们的分析中，整合素在 RGD-整合素对接位点周围和附近预测有钙和金属结合位点，这表明 RGD-整合素相互作用可能以钙依赖性方式发生。整合素在肺中的更高表达及其先前已知的高结合亲和力 (~K SARS-CoV-2刺突蛋白具有多个磷酸化位点，可诱导cAMP、PKC、Tyr信号通路。这些途径要么激活钙离子通道，要么被钙激活。事实上，在我们的分析中，整合素在 RGD-整合素对接位点周围和附近预测有钙和金属结合位点，这表明 RGD-整合素相互作用可能以钙依赖性方式发生。整合素在肺中的更高表达及其先前已知的高结合亲和力 (~K SARS-CoV-2刺突蛋白具有多个磷酸化位点，可诱导cAMP、PKC、Tyr信号通路。这些途径要么激活钙离子通道，要么被钙激活。事实上，在我们的分析中，整合素在 RGD-整合素对接位点周围和附近预测有钙和金属结合位点，这表明 RGD-整合素相互作用可能以钙依赖性方式发生。整合素在肺中的更高表达及其先前已知的高结合亲和力 (~K 在我们的分析中预测 RGD-整合素对接位点周围和附近的金属结合位点，这表明 RGD-整合素相互作用可能以钙依赖性方式发生。整合素在肺中的更高表达及其先前已知的高结合亲和力 (~K 在我们的分析中预测 RGD-整合素对接位点周围和附近的金属结合位点，这表明 RGD-整合素相互作用可能以钙依赖性方式发生。整合素在肺中的更高表达及其先前已知的高结合亲和力 (~K_{病毒 RGD 基序的D}  = 4.0 nM）可以作为 SARS-CoV-2 高传染性的可能解释。相反，人ACE2在肺部表达较低，结合亲和力高（~K _D = 15 nM) 单独的尖峰 RBD 不能表现出明显的病毒宿主附着。这表明除了人类 ACE2 之外，可能还存在另一种或替代的 SARS-CoV-2 受体。一个以前从未报道过的高度相关的证据证实了 RGD-整合素介导的病毒-宿主附着是一种释放的细胞因子风暴，它是由于 TNF-α 和 IL-6 激活而引起的；和整合素在其激活中的作用也已确立。总而言之，目前的研究强调了钙和其他二价离子在病毒侵入宿主细胞的 RGD-整合素相互作用中的可能作用，并表明降低肺中的二价离子可以避免病毒与宿主细胞的附着。