Exploiting glycosylation against COVID-19

In this project, we aim to expand our understanding on and exploit the essentiality of protein N-glycosylation for the control of SARS-CoV-2 transmission. N-glycosylation is the most common eukaryotic post-translational modification of proteins; it plays important roles, including protein folding and targeting as well as cell function. All SARS-CoV-2 proteins are predicted to be N-glycosylated, specially the surface homotrimeric Spike protein, which has been confirmed to have 22 N-glycans per monomer and whose structures have been recently determined. It is well known from similar coronaviruses (e.g., SARS-CoV, M-CoV) that surface glycans are important to modulate binding to the host receptor ACE2, and to reduce the accessibility of neutralising antibodies by hindering immunogenic epitopes. Although a lot of information has been obtained on the glycan structures of the Spike protein, to our knowledge, few functional studies on SARS-CoV-2 glycosylation have been performed so far. We hypothesise that interrupting the glycosylation of SARS-CoV-2 and/or host proteins will prevent viral infection and also render the virus more susceptible to the human immune system. We will do this using mainly two approaches: 1) by pharmacological inhibition of the N-glycosylation machinery and 2) by mutagenising specific N-glycan sequons on the virus Spike protein. We intend to translate the generated data into novel glycan-based therapeutics including repurposed glycosylation inhibitors to treat the disease. Our studies may also generate attenuated vaccine strains to prevent COVID-19 transmission.