Calcium dobesilate reduces SARS-CoV-2 entry into endothelial cells by inhibiting virus binding to heparan sulfate

Abstract

Recent reports demonstrate that SARS-CoV-2 utilizes cell surface heparan sulfate as an attachment factor to facilitate the initial interaction with host cells. Heparan sulfate interacts with the receptor binding domain of SARS-CoV-2 spike glycoprotein, and blocking this interaction can decrease cell infection. 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. 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. Using lentiviral SARS-CoV-2 spike protein pseudotyped particles we show that CaD could significantly reduce pseudovirus uptake into endothelial cells. On the contrary, CaD did not affect cell infection with VSVG-expressing lentivirus. CaD could also prevent retention of SARS-CoV-2 spike protein in ex vivo perfused mouse kidney. Using microfluidic culture of endothelial cells under flow, we show that CaD prevents spike protein interaction with heparan sulfate glycocalyx. Since CaD has no adverse side effects and is approved in humans for other medical indications, our findings can rapidly translate into clinical studies.

The D405N Mutation in the Spike Protein of SARS-CoV-2 Omicron BA.5 Inhibits Spike/Integrins Interaction and Viral Infection of Human Lung Microvascular Endothelial Cells

“…Proteome analysis confirmed a dramatic remodeling of SARS-CoV-2-infected HL-mECs, whereas inhibition of Spike RGD/integrins interaction resulted in blocking SARS-CoV-2 infection and in a complete recovery of viral-induced HL-mEC dysfunction [ 20 , 21 ]. More recently, other studies confirmed the capability of SARS-CoV-2 to infect different ECs [ 59 , 60 , 61 ] and defined the role of vimentin [ 62 ] and heparan sulfates [ 63 ] in maintaining and increasing the binding affinity of the viral Spike protein to the EC surface, facilitating SARS-CoV-2 entry.…”

Study protocol for assessment of the efficacy of calcium dobesilate versus placebo on SARS-CoV-2 viral load in outpatients with COVID-19 (CADOVID study): a randomised, placebo-controlled, double-blind, monocentric phase II trial

“…Preclinical results using lentiviral pseudotyped particles demonstrated that CaD interferes with the binding of SARS-CoV-2 spike protein to heparan sulphate and significantly reduced its uptake in cultured endothelial cells. 5 By contrast, CaD effects on cell infection were not mediated by cell toxicity or the inhibition of endocytosis.…”