The Distal Polybasic Cleavage Sites of SARS-CoV-2 Spike Protein Enhance Spike Protein-ACE2 Binding

Qiao, Botao; Cruz, Mónica Olvera de la

doi:10.1101/2020.06.09.142877

Cited by 5 publications

(8 citation statements)

References 44 publications

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“…The contradictory result suggests that the high transmissivity of SARS-CoV-2 may not rely solely on the receptor-binding domains. Our recent multiscale simulations at all-atom and coarse-grained resolutions supported that the O-linked residues, which are distributed approximately 10 nm from SARS-CoV-2 RBD-ACE2 contact region, can enhance RBD–ACE2 binding . This is in line with an earlier experimental work that the mutation of T 678 NSPRRAR 685 to a variant with T 678 –IL–R 685 of a murine leukemia virus decreased the transduction efficiency of human ACE2-expressing baby hamster kidney cells.…”

Section: Results and Discussionsupporting

confidence: 89%

“…Our recent work supported that in addition to the spike protein–ACE2 binding, the O-liked glycan residues can promote binding of SARS-CoV-2 with cell membranes, leading to fast cell entry. A negatively charged peptide was designed to charge neutralize the positively charged polybasic cleavge site, which consequently destabilized the SARS-CoV-2 spike protein RBD binding to the ACE2 receptor …”

Section: Results and Discussionmentioning

confidence: 99%

“…As shown in Figure 8, analysis of the outer surface of ACE2 supports that it is oppositely charged: around 20% of the ACE2 outer surface is negatively charged, which surpasses the probability of positively charged surface amino acids of 10%, in line with the face the ACE2 is highly negatively charged. 52 The oppositely charged feature between ACE2 and the receptor-binding domains of both spike proteins favor the binding of the virus and human cell membranes, which is required for cell entry.…”

Section: Resultsmentioning

confidence: 99%

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Protein Surface Printer for Exploring Protein Domains

Yang

Qiao

Cruz

2020

J. Chem. Inf. Model.

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The surface of proteins is vital in determining protein functions. Herein, a program, Protein Surface Printer(PSP), is built that performs multiple functions in quantifying protein surface domains. Two proteins, PETase and cytochrome P450, are used to validate that the program supports atomistic simulations with different combinations of programs and force fields. A case study is conducted on the structural analysis of the spike proteins of SARS-CoV-2 and SARS-CoV, and the human cell receptor ACE2.Although the surface domains of both spike proteins are highly similar, their receptor binding domains(RBDs) and the O-linked glycan domains are structurally different.Statistically, the outer surface of ACE2 displays less correlation with the RBD of SARS-CoV-2 than that of SARS-CoV. The O-linked glycan domain of SARS-CoV-2 is highly 1 . CC-BY-NC-ND 4.

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Section: Results and Discussionsupporting

confidence: 89%

Section: Results and Discussionmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Protein Surface Printer for Exploring Protein Domains

Yang

Qiao

Cruz

2020

J. Chem. Inf. Model.

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“…Mutations in the S protein that are distal from the RBD also impact on viral transmission ( Walls et al, 2020 ; Korber et al, 2020 ; Yuan et al, 2020 ). Non-RBD polybasic cleavage sites, including S1/S2 loop ( Hoffmann et al, 2020a ), have been described on SARS-CoV-2 S protein ( Qiao and Olvera de la Cruz, 2020 ) and may also be a site of potential interaction with astodrimer sodium.…”

Section: Discussionmentioning

confidence: 99%

Virucidal and antiviral activity of astodrimer sodium against SARS-CoV-2 in vitro

et al. 2021

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An effective response to the ongoing coronavirus disease (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) will involve a range of complementary preventive modalities. The current studies were conducted to evaluate the in vitro SARS-CoV-2 antiviral and virucidal (irreversible) activity of astodrimer sodium, a dendrimer with broad spectrum antimicrobial activity, including against enveloped viruses in in vitro and in vivo models, that is marketed for antiviral and antibacterial applications. We report that astodrimer sodium inhibits replication of SARS-CoV-2 in Vero E6 and Calu-3 cells, with 50% effective concentrations (EC 50 ) for i) reducing virus-induced cytopathic effect of 0.002 to 0.012 mg/mL in Vero E6 cells, and ii) infectious virus release by plaque assay of 0.019 to 0.032 mg/mL in Vero E6 cells and 0.031 to 0.037 mg/mL in Calu-3 cells. The selectivity index (SI) in these assays was as high as 2197. Astodrimer sodium was also virucidal, irreversibly reducing SARS-CoV-2 infectivity by >99.9% (>3 log 10 ) within 1 minute of exposure, and up to >99.999% (>5 log 10 ) shown at astodrimer sodium concentrations of 10 to 30 mg/mL in Vero E6 and Calu-3 cell lines. Astodrimer sodium also inhibited infection in a primary human airway epithelial cell line. The data were similar for all investigations and were consistent with the potent antiviral and virucidal activity of astodrimer sodium being due to irreversible inhibition of virus-host cell interactions, as previously demonstrated for other viruses. Further studies will confirm if astodrimer sodium binds to SARS-CoV-2 spike protein and physically blocks initial attachment of the virus to the host cell. Given the in vitro effectiveness and significantly high SI, astodrimer sodium warrants further investigation for potential as a topically administered agent for SARS-CoV-2 therapeutic applications.

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“…Mutations in the S protein that are distal from the RBD also impact on viral transmission (Walls et al, 2020;Korber et al, 2020;Yuan et al, 2020). Non-RBD polybasic cleavage sites, including S1/S2 loop (Hoffmann et al, 2020a), have been described on SARS-CoV-2 S protein (Qiao and Olvera de la Cruz, 2020) and may also be a site of potential interaction with astodrimer sodium. SARS-CoV-2 utilizes the ACE2 receptor for viral infection of host cells (Hoffmann et al, 2020b).…”

Section: Discussionmentioning

confidence: 99%

Virucidal and Antiviral Activity of Astodrimer Sodium against SARS-CoV-2 in Vitro

et al. 2021

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An effective response to the ongoing coronavirus disease (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) will involve a range of complementary preventive modalities. The current studies were conducted to evaluate the in vitro SARS-CoV-2 antiviral and virucidal activity of astodrimer sodium, a dendrimer with broad spectrum antimicrobial activity, including against enveloped viruses in in vitro and in vivo models, that is marketed for antiviral and antibacterial applications. We report that astodrimer sodium inhibits replication of SARS-CoV-2 in Vero E6 and Calu-3 cells, with 50% effective concentrations (EC50) for i) reducing virus-induced cytopathic effect of 0.002 to 0.012 mg/mL in Vero E6 cells, and ii) infectious virus release by plaque assay of 0.019 to 0.032 mg/mL in Vero E6 cells and 0.031 to 0.037 mg/mL in Calu-3 cells. The selectivity index (SI) in these assays was as high as 2197. Astodrimer sodium was also virucidal, reducing SARS-CoV-2 infectivity by >99.9% (>3 log10) within 1 minute of exposure, and up to >99.999% (>5 log10) shown at astodrimer sodium concentrations of 10 to 30 mg/mL in Vero E6 and Calu-3 cell lines.Astodrimer sodium also inhibited infection in a primary human airway epithelial cell line. The data were similar for all investigations and were consistent with the potent antiviral and virucidal activity of astodrimer sodium being due to inhibition of virus-host cell interactions, as previously demonstrated for other viruses. Further studies will confirm if astodrimer sodium binds to SARS-CoV-2 spike protein and physically blocks initial attachment of the virus to the host cell. Given the in vitro effectiveness and significantly high SI, astodrimer sodium warrants further investigation for potential as a nasally administered or inhaled antiviral agent for SARS-CoV-2 prevention and treatment applications.

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The Distal Polybasic Cleavage Sites of SARS-CoV-2 Spike Protein Enhance Spike Protein-ACE2 Binding

Cited by 5 publications

References 44 publications

Protein Surface Printer for Exploring Protein Domains

Protein Surface Printer for Exploring Protein Domains

Virucidal and antiviral activity of astodrimer sodium against SARS-CoV-2 in vitro

Virucidal and Antiviral Activity of Astodrimer Sodium against SARS-CoV-2 in Vitro

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