Rapid Degradation of SARS-CoV-2 Spike S Protein by A Specific Serine Protease

Liu, Jiankai; Kan, Mujie; Zhang, Lianzhi; Yue, Yuan; Wang, Shaohua; Hong, Ming; Hong, Xinyu

doi:10.3390/molecules27061882

Cited by 3 publications

(1 citation statement)

References 32 publications

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“…Compared to Wuhan S, the D614G mutant was indeed more reactive with Covi-10, 11, 17, 21, and 24, whereas Covi-9 was not bound ( Figure 2 j). The S1 subunit of the SARS-CoV-2 spike protein is prone to proteases, which results in degradation [ 77 ]. The Hexapro spike, based on a soluble Wuhan S, contained six proline substitutions (F817P, A892P, A899P, A942P, K986P, and V987P) that counteract such thermal instability and degradation [ 78 ].…”

Section: Resultsmentioning

confidence: 99%

Discordant Antigenic Properties of Soluble and Virion SARS-CoV-2 Spike Proteins

Kumar,

Dasgupta,

Sajadi

et al. 2024

Viruses

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Efforts to develop vaccine and immunotherapeutic countermeasures against the COVID-19 pandemic focus on targeting the trimeric spike (S) proteins of SARS-CoV-2. Vaccines and therapeutic design strategies must impart the characteristics of virion S from historical and emerging variants onto practical constructs such as soluble, stabilized trimers. The virus spike is a heterotrimer of two subunits: S1, which includes the receptor binding domain (RBD) that binds the cell surface receptor ACE2, and S2, which mediates membrane fusion. Previous studies suggest that the antigenic, structural, and functional characteristics of virion S may differ from current soluble surrogates. For example, it was reported that certain anti-glycan, HIV-1 neutralizing monoclonal antibodies bind soluble SARS-CoV-2 S but do not neutralize SARS-CoV-2 virions. In this study, we used single-molecule fluorescence correlation spectroscopy (FCS) under physiologically relevant conditions to examine the reactivity of broadly neutralizing and non-neutralizing anti-S human monoclonal antibodies (mAbs) isolated in 2020. Binding efficiency was assessed by FCS with soluble S trimers, pseudoviruses and inactivated wild-type virions representing variants emerging from 2020 to date. Anti-glycan mAbs were tested and compared. We find that both anti-S specific and anti-glycan mAbs exhibit variable but efficient binding to a range of stabilized, soluble trimers. Across mAbs, the efficiencies of soluble S binding were positively correlated with reactivity against inactivated virions but not pseudoviruses. Binding efficiencies with pseudoviruses were generally lower than with soluble S or inactivated virions. Among neutralizing mAbs, potency did not correlate with binding efficiencies on any target. No neutralizing activity was detected with anti-glycan antibodies. Notably, the virion S released from membranes by detergent treatment gained more efficient reactivity with anti-glycan, HIV-neutralizing antibodies but lost reactivity with all anti-S mAbs. Collectively, the FCS binding data suggest that virion surfaces present appreciable amounts of both functional and nonfunctional trimers, with neutralizing anti-S favoring the former structures and non-neutralizing anti-glycan mAbs binding the latter. S released from solubilized virions represents a nonfunctional structure bound by anti-glycan mAbs, while engineered soluble trimers present a composite structure that is broadly reactive with both mAb types. The detection of disparate antigenicity and immunoreactivity profiles in engineered and virion-associated S highlight the value of single-virus analyses in designing future antiviral strategies against SARS-CoV-2.

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Section: Resultsmentioning

confidence: 99%

Discordant Antigenic Properties of Soluble and Virion SARS-CoV-2 Spike Proteins

Kumar,

Dasgupta,

Sajadi

et al. 2024

Viruses

View full text Add to dashboard Cite

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Immunogenicity of intraperitoneal and intranasal liposome adjuvanted VLP vaccines against SARS-CoV-2 infection

Chulanetra,

Punnakitikashem,

Mahasongkram

et al. 2024

Sci Rep

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Immunogenicity of intraperitoneal and intranasal liposome adjuvanted VLP vaccines against SARS-CoV-2 infection

Chulanetra,

Punnakitikashem,

Mahasongkram

et al. 2024

Preprint

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Humans get SARS-CoV-2 infection through inhalation; thus, vaccine that induces protective immunity at the virus entry site is appropriate for early control of the infection. In this study, two anionic liposome-adjuvanted VLPs vaccines made of full-length S, M and E proteins SARS-CoV-2 were formulated. S1-S2 junction of S protein displayed on VLPs of one vaccine (L-SME-VLPs) contained furin cleavage site, while VLPs of another (L-S¢ME-VLPs) did not. Both vaccines were similarly/equally immunogenic in mice. Mice immunized parenterally with the vaccines had principally serum IgG3 neutralizing antibodies, while mice immunized intranasally produced predominantly specific Th1-antibody isotypes (IgG2a and/or IgG2b) in bronchoalveolar lavage samples. IgG3 isotype is known to be highly efficient in complement activation, opsonophagocytic activities, and antibody-dependent cell-mediated cytotoxicity, which causes virus clearance upon infection. Nevertheless, complement fixation and immune-complex formation may exacerbate tissue inflammation, cytokine storm, and lung immunopathology in the SARS-CoV-2-infecting host, which exacerbate the COVID-19 morbidity. Th1 antibodies are less efficient in complement fixation and phagocytic activity but exhibit stronger anti-viral effects than other antibody isotypes; thus, confer protection with minimal immunopathology upon new infection. The intranasal liposome-adjuvanted VLP vaccines should be tested further towards the clinical use as effective, safe, and better compliant vaccines against SARS-CoV-2.

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Rapid Degradation of SARS-CoV-2 Spike S Protein by A Specific Serine Protease

Cited by 3 publications

References 32 publications

Discordant Antigenic Properties of Soluble and Virion SARS-CoV-2 Spike Proteins

Discordant Antigenic Properties of Soluble and Virion SARS-CoV-2 Spike Proteins

Immunogenicity of intraperitoneal and intranasal liposome adjuvanted VLP vaccines against SARS-CoV-2 infection

Immunogenicity of intraperitoneal and intranasal liposome adjuvanted VLP vaccines against SARS-CoV-2 infection

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