Glycosaminoglycans induce conformational change in the SARS-CoV-2 Spike S1 Receptor Binding Domain.

The glycosaminoglycan (GAG) class of polysaccharides are utilised by a plethora of microbial pathogens as receptors for adherence and invasion. The GAG heparin prevents infection by a range of viruses if added exogenously, including the S-associated coronavirus strain HSR1 and more recently we have shown it inhibits cellular invasion by SARS-CoV-2. Heparin has found widespread clinical use as anticoagulant drug and this molecule is structurally similar to that of another GAG, heparan sulphate (HS), for which it is commonly used as an experimental proxy to mimic the properties of HS. We have previously demonstrated that unfractionated heparin and low molecular weight heparins binds to the Spike (S1) protein receptor binding domain, induces distinct conformational change and we have further explored the structural features of heparin with regard to these interactions. In this article, previous research is expanded to include a broader range of GAG family members. This research demonstrates that GAGs, other than those of heparin (or its derivatives), can also interact with the SARS-CoV-2 Spike S1 receptor binding domain and induce distinct conformational changes within this region. These findings pave the way for future research into next-generation, tailor-made, GAG-based antiviral agents, against SARS-CoV-2 and other members of the Coronaviridae.