High-Sulfated Glycosaminoglycans Prevent Coronavirus Replication

Abstract

Coronaviruses (CoVs) are common among humans and many animals, causing respiratory or gastrointestinal diseases. Currently, only a few antiviral drugs against CoVs are available. Especially for SARS-CoV-2, new compounds for treatment of COVID-19 are urgently needed. In this study, we characterize the antiviral effects of two high-sulfated glycosaminoglycan (GAG) derivatives against SARS-CoV-2 and bovine coronaviruses (BCoV), which are both members of the Betacoronavirus genus. The investigated compounds are based on hyaluronan (HA) and chondroitin sulfate (CS) and exhibit a strong inhibitory effect against both CoVs. Yield assays were performed using BCoV-infected PT cells in the presence and absence of the compounds. While the high-sulfated HA (sHA3) led to an inhibition of viral growth early after infection, high-sulfated CS (sCS3) had a slightly smaller effect. Time of addition assays, where sHA3 and sCS3 were added to PT cells before, during or after infection, demonstrated an inhibitory effect during all phases of infection, whereas sHA3 showed a stronger effect even after virus absorbance. Furthermore, attachment analyses with prechilled PT cells revealed that virus attachment is not blocked. In addition, sHA3 and sCS3 inactivated BCoV by stable binding. Analysis by quantitative real-time RT PCR underlines the high potency of the inhibitors against BCoV, as well as B.1-lineage, Alpha and Beta SARS-CoV-2 viruses. Taken together, these results demonstrated that the two high-sulfated GAG derivatives exhibit low cytotoxicity and represent promising candidates for an anti-CoV therapy.

Polysaccharides and Lectins: A Natural Complementary Approach against the SARS-CoV-2 Pandemic

“…The bovine low-sulfated chondroitin sulfate sCS3 was also reported to efficiently inhibit in vitro the viral replication of Alpha and Beta SARS-CoV-2 and the related bovine coronavirus BCoV at low IC 50 concentrations of 1.756 µM [76]. Interesting, in this study, assessing also the very efficient antiviral activity of another GAG, the modified high-sulfated hyaluronan sHA3, is the observation that the molecular weight and structure particularities of the disaccharide-repeating units determine the efficiency of the binding behaviors of sHA3 and sCS3, which have a similar degree of sulfation [76].…”

Polymers Inspired by Heparin and Heparan Sulfate for Viral Targeting

“…A more recent example of the chemical synthesis of an sGAG mimetic was reported by Möller and co-workers, who produced fully sulfated HA and CS analogues for biological evaluation . Inhibition studies with SARS-CoV-2 infections showed greater inhibition potential of the fully sulfated HA analogue with an SI = 232.68 compared to the fully sulfated CS analogue (SI = 82.39) despite having the same degree of sulfation.…”

Targeting of Glycosaminoglycans in Genetic and Inflammatory Airway Disease

“…Furthermore, studies have shown that hospitalized COVID-19 patients treated with low-molecular-weight heparin or ultra-low-molecular-weight heparin had improved mortality [ 135 , 136 ]. Highly sulphated HS- and CS-based compounds have also been developed for testing in COVID-19 treatment to block HS proteoglycan interaction with SARS-CoV-2 [ 137 ]. The compounds were found to inhibit SARS-CoV-2 growth in cells infected with the virus especially if the compounds were added during adsorption phase.…”