The Tan lab at the Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical college recently carried out an exploratory research into the infection mechanism of coronaviruses from an innovative perspective, i.e., by systematically comparing the binding of the SARS-CoV, MERS-CoV, SARS-CoV-2 S protein subunits, full-length molecules and their trimers to different heparan sulfate (HS) structures and oligosaccharides, through the collaboration with the Cui lab at the Institute of Pathogen Biology. This study, for the first time, revealed the common structural features required for the binding of the three viruses to glycans, which provides a new direction for the search of drugs against them. The article describing these findings appeared online January 19, 2021 in the journal Science Bulletin with the title“Binding of the SARS-CoV-2 Spike Protein to Glycans”.
In the past 20 years, the outbreaks of SARS-CoV, MERS-CoV and SARS-CoV-2 have seriously endangered human health and caused the deaths of millions of people and threatened the financial stability worldwide. In order to effectively combat these viruses, a more comprehensive understanding of their infection processes is required. Many viruses use cell-surface glycans as attachment factors to initiate infection. These glycans mainly include sialylated oligosaccharides that are covalently attached to proteins and lipids, and HS glycosaminoglycans. When specific glycan structures are responsible for virus entry into host cells, such glycans usually have the potential to be developed into new drugs to treat infections. A well-known example in this regard is the development of oseltamivir as an oral therapeutic to treat influenza infection. The three lethal coronaviruses SARS-CoV, MERS-CoV and SARS-CoV-2 may also first interact with specific glycans on the surface of susceptible host cells and this initial attachment may promote the subsequent binding of these virus to their high-affinity entry receptors ACE2 and DPP4. However, due to the difficulties associated with the studies involving glycans, very little prior information was available about the interactions between coronaviruses and HS/oligosaccharides.
To address this knowledge gap, at the beginning of 2020, the Tan lab initiated a collaborative study with the Cui lab on the interactions of coronaviruses with glycans using surface plasmon resonance and isothermal titration calorimetry. By systematically comparing the binding of the spike proteins (S proteins), their subunits and domains to a diverse collection of glycans,they found that these three coronaviruses are different from influenza viruses in that they cannot bind sialylated oligosaccharides, but they can all bind HS, and the strength of the binding is directly related to the sulfation pattern of HS chains. More importantly, the study also revealed that a low-molecular-weight heparin drug Fondaparinux can bind to the S proteins of these three coronaviruses in a similar fashion. These results indicated that SARS-CoV, MERS-CoV and SARS-CoV-2 are likely to first attach to human cells through interactions with heparan sulfate chains at the initial stage of infection. Therefore, inhibiting the binding of S proteins to HS may be a useful way to control coronavirus infection and low molecular weight HS could act as a starting point for the development of such inhibitors.
Article link: https://www.sciencedirect.com/science/article/pii/S2095927321000463
