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At the end of 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel human coronavirus, emerged and rapidly caused a global pandemic. SARS-CoV-2 is the causative agent of coronavirus disease 2019 (COVID-19), which affects the respiratory tract and lungs of infected individuals. Due to the increased transmissibility of the SARS-CoV-2 virus compared to its previous versions, determining as fully as possible the various structural aspects of the virus became critical for the development of therapeutics and vaccines to combat this virus. Knowing the structures of viral proteins and their glycosylation is an essential foundation for the understanding of the mechanism of the disease. Glycopeptide analysis has been used to map the glycosylation of viral glycoproteins, including those of influenza and HIV. Thanks to the developments in the field over the last few decades, scientists were able to quickly develop therapeutics against SARS-CoV-2. This chapter discusses the four structural proteins of SARS-CoV-2, their glycosylation and modifications, and the techniques used to map SARS-CoV-2 glycosylation. 

Abstract The glycosylation on the spike (S) protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, modulates the viral infection by altering conformational dynamics, receptor interaction and host immune responses. Several variants of concern (VOCs) of SARS-CoV-2 have evolved during the pandemic, and crucial mutations on the S protein of the virus have led to increased transmissibility and immune escape. In this study, we compare the site-specific glycosylation and overall glycomic profiles of the wild type Wuhan-Hu-1 strain (WT) S protein and five VOCs of SARS-CoV-2: Alpha, Beta, Gamma, Delta and Omicron. Interestingly, both N- and O-glycosylation sites on the S protein are highly conserved among the spike mutant variants, particularly at the sites on the receptor-binding domain (RBD). The conservation of glycosylation sites is noteworthy, as over 2 million SARS-CoV-2 S protein sequences have been reported with various amino acid mutations. Our detailed profiling of the glycosylation at each of the individual sites of the S protein across the variants revealed intriguing possible association of glycosylation pattern on the variants and their previously reported infectivity. While the sites are conserved, we observed changes in the N- and O-glycosylation profile across the variants. The newly emerged variants, which showed higher resistance to neutralizing antibodies and vaccines, displayed a decrease in the overall abundance of complex-type glycans with both fucosylation and sialylation and an increase in the oligomannose-type glycans across the sites. Among the variants, the glycosylation sites with significant changes in glycan profile were observed at both theN-terminal domain and RBD of S protein, with Omicron showing the highest deviation. The increase in oligomannose-type happens sequentially from Alpha through Delta. Interestingly, Omicron does not contain more oligomannose-type glycans compared to Delta but does contain more compared to the WT and other VOCs. O-glycosylation at the RBD showed lower occupancy in the VOCs in comparison to the WT. Our study on the sites and pattern of glycosylation on the SARS-CoV-2 S proteins across the VOCs may help to understand how the virus evolved to trick the host immune system. Our study also highlights how the SARS-CoV-2 virus has conserved bothN- andO- glycosylation sites on the S protein of the most successful variants even after undergoing extensive mutations, suggesting a correlation between infectivity/ transmissibility and glycosylation.