SARS - CoV - 2 Attachment to Host Cells is Possibly Mediated via RGD - Inte grin Interaction in a Calcium - dependent Manner
Our study revealed that SARS-CoV-2 harbors a RGD motif in its receptor binding domain (RBD) and the motif is absent in all previously known SARS-CoVs. The RGD motif plays a key role in cell-cell adhesion. Integrins display high affinity for RGD motifs and are known to bind to RGD motifs. Gene expression profiling revealed that expression of integrins is significantly high in lung cells, in particular αvβ6, α5β1, αvβ8 and an ECM protein, ICAM1. However, the expression of ACE2, which is a known receptor for SARS-CoV-2, was found to be negligible. 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 for 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 suggesting RGD-integrins interaction occurs in calcium-dependent manner. The higher expression of integrins in lungs along with their previously known high binding affinity (~KD = 4.0nM) for virus RGD motif could serve as a possible explanation for high infectivity of SARS-CoV-2. On the contrary, the lower expression of human ACE2 in lungs and its low binding affinity (~KD= 15nM) for spike RBD suggests that human ACE2 is less likely to be a receptor for SARS-CoV-2, at least in lung cells. 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 highlighted the 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. Since, EDTA is well known chelating agent, we suggest pulmonary EDTA chelation therapy as a mean to phenotypically remodel the Ca+2 ion concentration in lungs to prevent RGD-integrin interaction which is dependent upon Ca+2 ion for facilitating virus-host cell attachment. The suggested therapy presents a novel, technically simple, quick, safe, affordable and effective solution to prevent SARS-CoV-2 infection and treat COVID 19, especially in the midst of global emergency when a specific treatment is inexistent.