Spike lv2/12/2024 ![]() Several viruses interact with sialic acids located on the ends of glycans found in glycolipids and glycoproteins 30. Many viral pathogens have evolved to utilize glycans as attachment factors, which facilitate the initial interaction with host cells, including alpha-, beta- and gammaherpesviruses 25– 27, influenza virus, immunodeficiency virus, and different coronaviruses (SARS-CoV-1 and MERS-CoV) 28, 29. Viruses and other infectious organisms must transgress the glycocalyx to engage receptors that mediate viral entry into host cells. ![]() The glycocalyx is a complex mixture of glycans and glycoproteins covering the endothelial cell surface. Another important factor that could potentially explain this controversy is the abundance of endothelial glycocalyx both in vivo and in vitro experimental systems 24. Some organ-specific endothelial cells such as from brain show high ACE2 levels even in normal conditions 23. Expression of ACE2 by endothelial cells has been documented 22. Organ-specific and regulated expression of ACE2 is important for cell infection with SARS-CoV-2 21. Whereas other investigation find no evidence for endothelial infection 19, 20. Multiple reports demonstrate infection of endothelium both, in vivo and in vitro 15– 18. There is still controversy existing whether SARS-CoV-2 infects the endothelium directly. These microvascular complications of SARS-CoV-2 infection are most likely responsible for the high rate of morbidity and mortality of infected patients 13, 14. Furthermore, recent report suggested that proteolytically released S1 domain of SARS-CoV-2 spike protein induces endothelial damage, vascular permeability and expression of PAI-1 and VEGF by lung microvascular endothelial cells 11, 12. Pro-inflammatory cytokines, elevated in patients with COVID-19, induce the loss of the normal antithrombotic and anti-inflammatory functions of endothelial cells, leading to coagulation dysregulation, complement and platelet activation, and leukocyte recruitment in the microvasculature 9. Therefore, it is reasonable to assume that endothelial dysfunction contributes to COVID-19-associated vascular inflammation. Higher levels of acute phase reactants (IL-6, C-reactive protein, and D-dimer) are also associated with severe SARS-CoV-2 infection. Endothelial activation results into elevated levels of pro-inflammatory cytokines-interleukin-1, interleukin-6 (IL-6) and tumor necrosis factor-α (TNFα), chemokines and antithrombotic factors-von Willebrand factor and factor VIII in these critically endangered patients 10. It seems that an inflammatory endothelial response that may involve the coagulation cascade and/or the complement pathway plays a vital role 8, 9. The clinical picture in these patients resembles the systemic inflammatory response syndrome (SIRS) with a strong microvascular component 4– 7. The underlying mechanisms of this severe form of the disease are not fully understood. However, in 20% of patients, infection with SARS-CoV-2 leads to life-threatening respiratory, cardiac, renal, and cerebral injury 1, 3. This form of infection is self-limiting and causes no serious threat to the infected person. Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is in most patients limited to bronchoalveolar epithelial cells and associated with local bronchopulmonary symptoms 1– 3. Since CaD has no adverse side effects and is approved in humans for other medical indications, our findings can rapidly translate into clinical studies. Using microfluidic culture of endothelial cells under flow, we show that CaD prevents spike protein interaction with heparan sulfate glycocalyx. CaD could also prevent retention of SARS-CoV-2 spike protein in ex vivo perfused mouse kidney. On the contrary, CaD did not affect cell infection with VSVG-expressing lentivirus. Using lentiviral SARS-CoV-2 spike protein pseudotyped particles we show that CaD could significantly reduce pseudovirus uptake into endothelial cells. We hypothesized that Calcium Dobesilate (CaD)-calcium salt of 2,5-dihydroxyphenylic acid-may also interfere with the binding of SARS-CoV-2 spike protein to heparan sulfate. We and others reported recently that the family of compounds of 2,5-dihydroxyphenylic acid interferes with the binding of the positively charged groove in growth factor molecules to negatively charged cell surface heparan sulfate. ![]() ![]() Heparan sulfate interacts with the receptor binding domain of SARS-CoV-2 spike glycoprotein, and blocking this interaction can decrease cell infection. Recent reports demonstrate that SARS-CoV-2 utilizes cell surface heparan sulfate as an attachment factor to facilitate the initial interaction with host cells.
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