Emerging COVID-19 coronavirus: glycan shield and structure prediction of spike glycoprotein and its interaction with human CD26

Abstract

The recent outbreak of pneumonia-causing COVID-19 in China is an urgent global public health issue with an increase in mortality and morbidity. Here we report our modelled homo-trimer structure of COVID-19 spike glycoprotein in both closed (ligand-free) and open (ligand-bound) conformation, which is involved in host cell adhesion. We also predict the unique N-and O-linked glycosylation sites of spike glycoprotein that distinguish it from the SARS and underlines shielding and camouflage of COVID-19 from the host the defence system. Furthermore, our study also highlights the key finding that the S1 domain of COVID-19 spike glycoprotein potentially interacts with the human CD26, a key immunoregulatory factor for hijacking and virulence. These findings accentuate the unique features of COVID-19 and assist in the development of new therapeutics.

Recombinant SARS-CoV-2 spike S1-Fc fusion protein induced high levels of neutralizing responses in nonhuman primates

“…Since the SARS-CoV-2 S1 protein is predicted to have at least 16 N-linked glycosylation sites [15], we chose mammalian cell CHO-K1 as the expression system to ensure the right glycosylation. CHO-K1 is also one of the most popular cell lines used to make human antibody drugs.…”

Structural interactions between pandemic SARS-CoV-2 spike glycoprotein and human Furin protease

“…It is quite interesting to notice that none of the previously known coronaviruses had this novel Furin protease cleavage site in the spike glycoprotein, which accentuates the novelty and uniqueness of SARS-CoV-2. In addition, previous reports on the glycosylation of spike glycoprotein show that Furin cleavage site in the SARS-CoV-2 spike glycoprotein is not targeted by the glycosylation, hence this cleavage loop is completely solvent-exposed (4). This further corroborates the potential attack of Furin protease over the S1/S2 cleavage site in the SARS-CoV-2 spike glycoprotein.…”

“…As these EM structures built on molecular replacement with SARS-CoV-1 (PDB: 6ACG), Furin cleavage sites in the spike protein is flexible and novel insertion only in the SARS-CoV-2, the EM structures lack this important region. Hence, for the molecular dynamics and simulation studies, we directed to use previously published and validated model structure of full-length SARS-CoV-2 spike glycoprotein (4) and published structure of human Furin (PDB: 1P8J or 1JXH) (11). The RMSD of the previously published model structure and Cryo-EM structure was 0.84, which suggests overall structural accuracy even with the presence of Furin cleavage sites.…”

“…Since the initial reports on this pneumonia-causing novel coronavirus (SARS-CoV-2) in Wuhan, China, mortality and morbidity are increasing exponentially around the globe despite several antiviral and antibody treatments (2). Most available neutralising antibodies in use are targeting the SARS-CoV-2 spike glycoprotein, which is essential for host cell adhesion via ACE2 and CD26 receptors (3, 4), but infection control is still insignificant. Meanwhile, several antiviral drugs (Ritonavir, Lopinavir, Chloroquine, Remdesivir and others) targeting different host and viral proteins are been clinically evaluating and repurposing to combat SARS-CoV-2 infection (2, 5).…”

“…In this regard, several epidemiological and evolutionary reports have highlighted the several unique sequence deletions and insertions in the SARS-CoV-2 genome compare to previous known SARS and Bat coronavirus (6, 7). Among the various genetic variations, insertion of Furin protease cleavage site in the spike glycoprotein (aa682 – aa689) is strikingly novel in SARS-CoV-2 (4, 8) and has not been found in other related coronaviruses (SARS-CoV-1, Bat-CoV, Pangolin) (MERS contain pseudo binding site) (Fig. S1A).…”