Targeting the GRP78-Dependant SARS-CoV-2 Cell Entry by Peptides and Small Molecules

Abstract

The global burden of infections and the rapid spread of viral diseases show the need for new approaches in the prevention and development of effective therapies. To this end, we aimed to explore novel inhibitor compounds that can stop replication or decrease the viral load of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), for which there is currently no approved treatment. Besides using the angiotensin-converting enzyme (ACE2) receptor as a main gate, the CoV-2 can bind to the glucose-regulating protein 78 (GRP78) receptor to get into the cells to start an infection. Here, we report potential inhibitors comprising small molecules and peptides that could interfere with the interaction of SARS-CoV-2 and its target cells by blocking the recognition of the GRP78 cellular receptor by the viral Spike protein. These inhibitors were discovered through an approach of in silico screening of available databases of bioactive peptides and polyphenolic compounds and the analysis of their docking modes. This process led to the selection of 9 compounds with optimal binding affinities to the target sites. The peptides (satpdb18674, satpdb18446, satpdb12488, satpdb14438, and satpdb28899) act on regions III and IV of the viral Spike protein and on its binding sites in GRP78. However, 4 polyphenols such as epigallocatechin gallate (EGCG), homoeriodictyol, isorhamnetin, and curcumin interact, in addition to the Spike protein and its binding sites in GRP78, with the ATPase domain of GRP78. Our work demonstrates that there are at least 2 approaches to block the spread of SARS-CoV-2 by preventing its fusion with the host cells via GRP78.

Role of Serine Proteases and Host Cell Receptors Involved in Proteolytic Activation, Entry of SARS-CoV-2 and Its Current Therapeutic Options

“…Thus, potent inhibitors including epigallocatechin gallate (EGCG) and various bioactipeptides (satpdb18674, satpdb18446, satpdb12488, satpdb14438, and satpdb28899) was tried to inhibit GRP78-S protein complex interaction. 69 Serum protein level of GRP78 was analyzed using case-control observational study in Turkey among 144 adult patients (Table 1). COVID-19 patients showed higher levels of GRP78 compared with control groups and ER stress induces an elevated level of GRP78 67 Morbidity of SARS-CoV-2 was elevated in COVID-19 patients who took angiotensin-receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs) because the expression of ACE2 is increased.…”

An Overview of Spike Surface Glycoprotein in Severe Acute Respiratory Syndrome–Coronavirus

“…Allam et al, performed an in silico screening of a library of compounds and identified four potential phytochemicals (polyphenols, viz ., epigallocatechin gallate (EGCG; 27), homoeriodictyol (28), isorhamnetin (29), and curcumin (30)) and five peptides (satpdb18674 (31), satpdb18446 (32), satpdb12488 (33), satpdb14438 (34), and satpdb28899 (35)) that inhibited the interaction of the SARS-CoV-2 S protein with GRP78 using molecular docking approaches ( Allam et al, 2020 ), Quimque et al docked 97 antiviral molecules from fungi secondary metabolites followed by molecular dynamics simulation and in silico ADMET prediction. Three fumiquinazoline alkaloids, scedapin C (36), quinadoline B (37), and nor-quinadoline A (38); the polyketide isochaetochromin D1 (39); and the terpenoid 11a-dehydroxyisoterreulactone A (40) exhibited strong in silico inhibition against GRP78 of SAR-CoV-2 ( Quimque et al, 2020 ) ( Figure 10 ).…”

The Impact of Endoplasmic Reticulum-Associated Protein Modifications, Folding and Degradation on Lung Structure and Function

“…Cell surface-GRP78 is upregulated in many cancer cells, including breast and prostate cancers and has become a target for cancer therapy ( Tsai and Amy, 2018 ), In infection, cell surface-GRP78 can assist viral attachment and entry into the cell by binding pathogenic proteins, including the spike (S) protein on the outer envelope of viruses and coat proteins on fungi ( Elfiky et al, 2020 ). Cell surface-GRP78 is expressed on several mammalian cells, including the human airway cell lines, A549, Beas2B, and Calu3 and is upregulated by a variety of viruses ( Nain et al, 2017 ; Chu et al, 2018 ; Elfiky et al, 2020 ) The receptor-binding domain of the S protein of different members of the CoV family can interact with angiotensin-converting enzyme-2 (ACE2), dipeptidyl peptidase-4, and cell surface-GRP78, allowing the membranes of the virus and target cell to fuse ( Chu et al, 2018 ; Allam et al, 2020 ). In Middle East Respiratory Syndrome (MERS)-CoV, cell suface-GRP78 does not independently allow nonpermissive cells to be infected by the virus, but facilitates entry of the virus into permissive cells in the presence of dipeptidyl peptidase-4 ( Chu et al, 2018 ).…”

“…Serum GRP78 levels are also reported to be higher in COVID-19 positive patients compared to COVID-19 negative patients with pneumonia and healthy controls ( Sabirli et al, 2021 ). Several candidate peptides and small molecules targeting the GRP78-binding site on the S protein of SARS-CoV-2 and the viral docking site on GRP78 have been identified, of which Satpdb18674 and epigallocatechin gallate are predicted to be the most effective ( Allam et al, 2020 ). As of yet, no follow up studies have been performed to experimentally confirm the effectiveness of targeting the GRP78-S protein binding sites to inhibit SARS-CoV-2 infection and reduce viral load.…”