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. 2020 Oct 21:14:1177932220965505.
doi: 10.1177/1177932220965505. eCollection 2020.

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

Loubna Allam  1 , Fatima Ghrifi  1 , Hakmi Mohammed  1 , Naima El Hafidi  1 , Rachid El Jaoudi  1 , Jaouad El Harti  2 , Badreddine Lmimouni  3 , Lahcen Belyamani  4 , Azeddine Ibrahimi  1
Affiliations

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

Loubna Allam et al. Bioinform Biol Insights. .

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.

Keywords: GRP78; SARS-CoV-2; Spike; inhibitors; peptide; small molecule.

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Conflict of interest statement

Declaration of conflicting interests:The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1.
Figure 1.
Binding modes of 3 candidate peptides housed at the GRP78-binding regions on SARS-CoV-2 Spike (PDB ID: 6LZG). The spike is represented here by white surface (top) and green cartoon (bottom). The interacting residues of the Spike protein are colored in orange in the surface representation. The peptide satpdb18674 residues SER-4, TYR-2, and PHE-5 interacted with the CYS-480, ASN-481, and PHE-486 of region IV of the Spike. Satpdb12488 residues MET-5, PHE-4, THR-13, ASP-16, THR-2, THR-3, and TYR-15 interacted with TYR-473, TYR-453, ALA-475, and ARG-403 from region III and satpdb28899 (ARG-1, ASP-20, LEU-19, GLU-17, THR-15, and SER-16) interacted with GLU-484, ARG-466, TYR-351, SER-349, and ARG-346 from the same region. GRP78 indicates glucose-regulating protein 78; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
Figure 2.
Figure 2.
Binding modes of the 5 candidate peptides housed in the substrate-binding region of GRP78 (PDB: 5E84). They are represented here by white surface (top) and green cartoon (bottom). The interacting residues of GRP78 are colored in orange in the surface representation. The interaction of the satpdb18674 peptide residues (GLN-1, SER, and THR-7) with the residues (VAL-429, GLN-449, and SER-452) of the GRP78-binding site. The peptide satpdb18446 residues TYR-3, ASN-4, VAL-1, and THR-10 interacted with THR-434, VAL-429, GLN-449, and SER-452 of the same target. For satpdb12488 residues, ASP-19, THR-2, ASP-16, and MET-5 interacted with the THR-434, VAL-429, LYS-447, PHE-451, and SER-452 of the GRP78. The residues (ILE-13, SER-12, and THR-9) of satpdb14438 interacted with GRP78 residues THR-434, VAL-429, and THR-458. Finally, the peptide satpdb28899 residues ASP-20, LEU-19, SER-16, and THR-15 interacted with VAL-429 and THR-458 from the same region. The 5 compounds established multiple hydrogen bonds with the residues of the GRP78 substrate-binding pocket. Interactions with V429 and S452 were observed in the 5 peptides, except for satpdb28899 (V429 only). satpdb12488, satpdb14438, and satpdb18446 interacted with THR-434; satpdb14438 and satpdb28899 interacted with GLN-449; satpdb14438 and satpdb28899 interacted with THR-458; and satpdb12488 interacted with LYS-447 and PHE-451. GRP indicates glucose-regulating protein.
Figure 3.
Figure 3.
Modes of satpdb18674 binding to Spike protein and GRP78. (A) The interacting satpdb18674 residues GLN-1, SER-4, and THR-7 with the residues of the GRP78 site (VAL-429, GLN-449, and SER-452). (B) Interacting satpdb18674 residues SER-4, TYR-2, and PHE-5 with the residues from region IV of the Spike (CYS-480, ASN-481, and PHE-486). The interacting residues of GRP78 are colored in light orange, and those of the Spike are colored in dark orange (surface representation). The satpdb18674 peptide interacted, respectively, with the residues of the GRP78 site and those of the region IV of Spike. GRP78 indicates glucose-regulating protein 78.
Figure 4.
Figure 4.
Modes of polyphenols binding on the GRP78 site. The active site in GRP78 is colored orange in (a′, b′, c′, and d′). The 4 compounds established multiple hydrogen bonds with the residues at the active site of GRP78. All the compounds interacted with the Glu-427 residue, and other interactions were observed with Ser-455, Ser-452, Ile-450, Ala-454, Gln-458 for EGCG (a, a′). Homoeriodictyol (b, b′) interacted with Gly-430, Ile-450, and Val-429; isorhamnetin (c, c′) interacted with Gly-430, Ser-448, and Gln-458; and curcumin (d, d′) interacted with Ser-425, Ile-450, and Thr-441. The best affinity was attributed to EGCG (–10.5 kcal/mol). EGCG interacts through the H bonds with Glu-427, Gln-458, Ser-455, Ala-454 and a hydrophobic bond with Ile-450; homoeriodictyol and isorhamnetin establish the same H bonds with Glu-427, Glu-430, Ser-448, and Gln-485; curcumine interact with 2 residues Glu-427 and Ile-450 through the H bonds and 2 hydrophobic bonds through Ser-425 and Thr-441. EGCG indicates epigallocatechin gallate; GRP78, glucose-regulating protein 78.
Figure 5.
Figure 5.
Modes of polyphenols binding in the GRP78/SARS-CoV-2 Spike interaction site (Spike side). The binding region of the Spike is colored in orange. The 4 compounds established multiple hydrogen bonds with the residues at the binding region of the Spike. Interactions with Lys-417, Asp-420, Asn-422, and Tyr-421 were observed for all compounds: EGCG (a, a′), homoeriodictyol (b, b′), curcumin (d, d′), except isorhamnetin (c, c′) that established H bonds with Pro-463 and Tyr-505 instead the Asn-420 and Lys-417; EGCG also interacted with Asn-460 and Lys-464. EGCG indicates epigallocatechin gallate; GRP78, glucose-regulating protein 78; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
Figure 6.
Figure 6.
Binding modes of the 4 selected candidates in the substrate-binding site of GRP78 ATPase domain (PDB: 5F1X). (a, a′) ATP; (b, b′) EGCG; (c, c′) homoeriodictyol; (d, d′) isorhamnetin; and (e, e′) curcumin. The ATP docking was used to define the key residues in the catalytic site (Asp-34, Thr-38, Thr-39, Ile-61, Glu-201, Asp-224, Phe-258, Gly-228, Gly-249, Asp-249, Gly-364, Ser-365, Ile-368, and Asp-39). The active site is colored in orange. The 4 molecules have established at least 6 hydrogen bonds with these residues in GRP78. The best affinity was attributed to EGCG (–10.2 kcal/mol), higher than that of ATP (–9.6 kcal/mol). All molecules interact through hydrogen bonds with Gly-228, Phe-258, Asp-224 residues; EGCG established 3 other H bonds with Gly-364, Ser-365, and Ile-368. Homoeriodictyol, isorhamnetin, and curcumine interact through hydrophobic bonds with Thr-38 and Thr-39. EGCG indicates epigallocatechin gallate; GRP78, glucose-regulating protein 78.
Figure 7.
Figure 7.
The strategy description targeting the different sites involved in the SARS/GRP78 interaction. Chemical molecules have been extracted from compound libraries (PubChem and SATPdb). Screening of these molecules (100 polyphenols and 40 peptides) was carried out by the docking method by AutoDock Vina and ClusPro server. This method offers a precise and efficient anchoring tool, which is based on empirical notation functions. It is based on the average binding energy scores in AutoDock Vina, and the root-mean-square deviation (RMSD) in ClusPro to generate clusters with the most probable models of the complex. Selection of structures based on energy minimization. GRP78 indicates glucose-regulating protein 78.
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References

    1. Gallagher TM, Buchmeier MJ. Coronavirus spike proteins in viral entry and pathogenesis. Virology. 2001;279:371-374. - PMC - PubMed
    1. Liu X, Wang Y, Liu Y, Chen H, Hu Y. Response of bacterial and fungal soil communities to Chinese fir (Cunninghamia lanceolate) long- monoculture plantations term. Front Microbiol. 2020;11:181. - PMC - PubMed
    1. Du L, Tai W, Zhou Y, Jiang S. Vaccines for the prevention against the threat of MERS-CoV. Expert Rev Vaccines. 2016;15:1123-1134. - PMC - PubMed
    1. Zhou Y, Jiang S, Du L. Prospects for a MERS-CoV spike vaccine. Expert Rev Vaccines. 2018;17:677-686. - PMC - PubMed
    1. Elfiky AA, Mahdy SM, Elshemey WM. Quantitative structure-activity relationship and molecular docking revealed a potency of anti-hepatitis C virus drugs against human corona viruses. J Med Virol. 2017;89:1040-1047. - PMC - PubMed

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