Recognition through GRP78 is enhanced in the UK, South African, and Brazilian variants of SARS-CoV-2; An in silico perspective

Abstract

New SARS-CoV-2 variants emerged in the United Kingdom and South Africa in December 2020 in concomitant with the Brazillian variant in February 2021 (B.1.1.248 lineage) and currently sparking worldwide during the last few months. The new strain 501.V2 in South Africa bears three mutations in the spike receptor-binding domain (RBD); K417 N, E484K, and N501Y, while the Brazilian B.1.1.248 lineage has 12 mutations. In the current study, we simulate the complex ACE2-SARS-CoV-2 spike RBD system in which the RBD is in the wild-type and mutated isoforms. Additionally, the cell-surface Glucose Regulated Protein 78 (CS-GRP78) associated with the ACE2-SARS-CoV-2 spike RBD complex (ACE2-S RBD) is modeled at the presence of these mutant variants of the viral spike. The results showed that E484K and N501Y are critical in viral spike recognition through either ACE2 or CS-GRP78. The mutated variants (the UK, South African, and Brazilian) of the spike RBD tightly bind to GRP78 more than in the case of the wild-type RBD. These results point to the potent role of GRP78 with ACE2 in the attachment of the new variants, which could be a key for the design of inhibitors to block SARS-CoV-2 attachment and entry to the host cell.

Pulmonary mucormycosis in the aftermath of critical COVID-19 in an immunocompromised patient: Mind the diagnostic gap

“…Elevated glucose levels impair the immune function in several ways, particularly by reducing the innate immune systems’ response towards invading pathogens [10] . Both SARS-CoV-2 and Mucorales species enter the endothelial cells through glucose regulated protein 78 (GRP78) [ 8 , 12 ], which is presented on the cell surface during cell stress, including glucose dysregulation and COVID-19 infection [8] . Dexamethasone has also been shown to upregulate GRP78 [13] .…”

“…Dexamethasone has also been shown to upregulate GRP78 [13] . A recent study suggests that the new SARS-CoV-2 variants bind more tightly to GRP78 than the original strains [12] , which might partly explain the increasing incidence of CAM.…”

GRP78: A possible relationship of COVID-19 and the mucormycosis; in silico perspective

“…Additionally, the new strain spikes of SARS-CoV-2 (alpha, beta, and gamma strains) show higher RMSF values for the C480–C488 region than the WT spike. A correlation between the elevated RMSF of this region and the predicted spike recognition by GRP78 is reported as well [ 17 , 18 ]. So, we suggest the CotH3 L396-N402 region to be the recognition element for CS-GRP78 on epithelial cells.…”

“…Moreover, GRP78 has been hypothesized to be responsible for the cross-vaccination reported for human coronaviruses [ 12 , 15 ]. The recognition of SARS-CoV-2 spike of the new variants alpha (UK variant VOC-202012/01), beta (South African 501.V2), and Gamma (Brazilian B.1.1.248) by cell-surface GRP78 is enhanced compared to the wildtype SARS-CoV-2 [ 17 , 18 ].…”

Potential antiviral properties of antiplatelet agents against SARS-CoV-2 infection: an in silico perspective

“…Residue interacts with π-stacking is blue-colored, while the orange residue is that interacts with salt bridges. Bold residues are the most common residues We previously reported the enhanced binding contribution of the cell-surface Glucose Regulated Protein 78 (CS-GRP78), also termed Heat Shock Protein A5 (HSPA5), to the newly emerged variants SARS-CoV-2 (UK, South African, and Brazilian) spike protein compared to the wildtype variant [44,45]. The predicted GRP78 recognition site of the spike is located in the C480-C488 region [46][47][48].…”