Aug 2026· Antiviral Research· Vol 254, pp.
106515
· 0 citations· 59 references
Medicine
TL;DR
SBP10 and SBP16 function as dual targeting engineered binding proteins that inhibit viral entry while attenuating complement-mediated inflammation, highlighting a promising therapeutic strategy for controlling SARS-CoV-2 infection and its associated immune dysregulation.
Abstract
The rapid evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and associated complement overactivation challenge current antiviral strategies that mainly target viral entry. This study aimed to develop dual targeting engineered binding proteins capable of simultaneously blocking viral infection and complement activation. Two proteins, SBP10 and SBP16, were engineered by integrating an ACE2-mimicking peptide with a mannose-binding lectin (MBL) domain. Binding affinity and antiviral activity were evaluated using biochemical and functional assays, including inhibition of S protein-ACE2 interaction, neutralization of multiple SARS-CoV-2 variants, and assessment of lectin pathway-mediated complement activation. Both SBP10 and SBP16 bound the spike protein with low-nanomolar affinity and effectively blocked its interaction with ACE2. The proteins exhibited broad-spectrum neutralizing activity against several variants, including Alpha, Beta, Delta, and Omicron. Moreover, they significantly suppressed spike-induced activation of the lectin complement pathway. In vivo experiments further demonstrated that treatment with SBP10 or SBP16 markedly reduced spike protein-induced lung injury. In conclusion, SBP10 and SBP16 function as dual targeting engineered binding proteins that inhibit viral entry while attenuating complement-mediated inflammation, highlighting a promising therapeutic strategy for controlling SARS-CoV-2 infection and its associated immune dysregulation.
HRBD demonstrated potent and broad-spectrum inhibition against Pangolin-CoV, SARS-CoV, SARS-CoV, SARS-CoV-2, and its variants, lowering the half-maximal inhibitory concentration (IC50) by approximately 1000-fold compared to the monomeric RBD.
Jintao Zou, Lingyu Su, Jiansheng Lu et al.· Antiviral Research· 0 citations
ABSTRACT Antibody-mediated entry (AME) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into monocytes and macrophages has been linked to activation of inflammatory phenotypes that are associated with severe coronavirus disease 2019 (COVID-19), but why only some antibodies mediate this entry while others do not is unknown. However, it has been demonstrated that conformational dynamics of the SARS-CoV-2 receptor-binding domain (RBD) are critical to viral entry, and that antibodies targeting the RBD can conformationally regulate these dynamics. Here, we identified four groups of RBD-specific monoclonal antibodies (mAbs) that target unique epitopes on the SARS-CoV-2 RBD and are also associated with different RBD conformational regulation and AME abilities. Steric clash quantification elucidated a structural basis for differences in conformational regulation by these antibody groups. We found that some, but not all, antibody groups were able to mediate entry into THP1-derived macrophages, and also found that this entry was inhibitable by antibodies in other groups. Collectively, these results suggest that there is a connection between RBD conformational regulation, epitope, and AME for antibodies targeting SARS-CoV-2. This connection improves understanding of the AME mechanism and how to inhibit AME for SARS-CoV-2, which has potential applications in the continued development of safe and effective vaccines and therapeutics for COVID-19 and related diseases. IMPORTANCE Antibody-mediated entry (AME) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into immune cells and resulting activation of inflammatory pathways is increasingly being associated with coronavirus disease 2019 (COVID-19) disease severity. Vaccination against COVID-19 remains one of our strongest tools to prevent these effects; vaccines continue to protect patients from both severe and long COVID-19 symptoms, and serum from vaccinated individuals was shown not to cause AME in immune cells in vitro. However, a lack of understanding about why some, but not all, antibodies cause AME limits our ability to actively prevent AME in antigen design. In this work, we identify characteristics that differentiate individual AME and non-AME antibodies. We also report that AME can be inhibited by other antibodies. Understanding these characteristics and differences between antibodies could allow us to add functionality to already effective vaccines by designing them to actively avoid eliciting AME antibodies and promote antibodies that inhibit AME and its downstream systemic effects. Antibody-mediated entry (AME) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into immune cells and resulting activation of inflammatory pathways is increasingly being associated with coronavirus disease 2019 (COVID-19) disease severity. Vaccination against COVID-19 remains one of our strongest tools to prevent these effects; vaccines continue to protect patients from both severe and long COVID-19 symptoms, and serum from vaccinated individuals was shown not to cause AME in immune cells in vitro. However, a lack of understanding about why some, but not all, antibodies cause AME limits our ability to actively prevent AME in antigen design. In this work, we identify characteristics that differentiate individual AME and non-AME antibodies. We also report that AME can be inhibited by other antibodies. Understanding these characteristics and differences between antibodies could allow us to add functionality to already effective vaccines by designing them to actively avoid eliciting AME antibodies and promote antibodies that inhibit AME and its downstream systemic effects.
Casey L Kiyohara, Sheamin Kim, W. Thomas· Microbiology spectrum· 0 citations
It is demonstrated that nanobodies targeting the PLpro/ISG15 interface can achieve synergistic antiviral and immunomodulatory effects, providing a proof-of-concept for a novel therapeutic approach to combat SARS-CoV-2 and potentially other emerging coronaviruses.
Guo-Long Liu, Jiantao Chen, Fang Wu et al.· Journal of Virology· 0 citations
The continuous evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) highlights the value of broad-spectrum antiviral strategies. Antibody-engineering approaches targeting conserved regions of the Spike protein may enhance neutralizing potency and breadth.
A human antibody (P23) against the Spike protein of SARS-CoV-2 was identified using a human antibody phage display library panning and screening for binding affinity and breadth against multiple coronavirus Spike proteins using surface plasmon resonance (SPR). The epitope of P23 was characterized using the S1 and S2 subunits of SARS-CoV-2 Spike protein and hydrogen–deuterium exchange mass spectrometry (HDX-MS). An IgG–like bispecific fusion protein (Bs-ACE2-P23) was engineered by fusing the extracellular domain (ECD) of human angiotensin-converting enzyme 2 (ACE2) to the N-terminus of the P23 heavy chain (HC). Neutralizing activity was evaluated against both pseudotyped and authentic SARS-CoV-2 variants.
P23 cross-bound Spike proteins from SARS-CoV-2 wild type (WT), D614G and JN.1 variants, Pangolin-CoV, Bat coronavirus RaTG13, and SARS-CoV-1, recognizing an epitope on the S2 subunit adjacent to the fusion peptide (FP). While P23 was ineffective against D614G-containing SARS-CoV-2 variants, Bs-ACE2-P23 exhibited markedly enhanced neutralization potency. This bispecific architecture also improved the neutralizing activity of another FP-targeting antibody.
We developed a bispecific fusion protein with potent broad-spectrum neutralizing activity against SARS-CoV-2 variants. This architecture provides a promising strategy for next-generation coronavirus biologics.
Zhi-Zhong Wei, Ximing Liu, Kailun Wang et al.· Antibody Therapeutics· 0 citations
The complement system is a major effector system of the humoral immune response, but its capacity to cooperate with antibodies to inhibit the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a host remains poorly characterized. Here, we combined authentic virus neutralization, antibody engineering, and single viral particle analysis by flow virometry to show that complement enhances antibody neutralization of SARS-CoV-2. Addition of complement increased neutralization titers of sera from convalescent individuals (n = 14), vaccinated individuals (n = 15), and individuals with hybrid immunity (n = 15) against D614G, BA.1, XBB.1.5, and JN.1 variants by up to 42-fold. D614G and BA.1 displayed a high level of neutralization, which was only slightly improved by adding complement. Conversely, neutralization of XBB.1.5 and JN.1 was weak but strongly enhanced by complement. Among the 32 JN.1 nonneutralizers, 22 regained detectable neutralization in the presence of complement. The enhancement mainly relied on cross-reactive anti-S2 antibodies, but monoclonal antibodies targeting the receptor binding domain and N-terminal domain could also be augmented. Viral inhibition required antibody Fc hexamerization, C1q recruitment, and C3 deposition, but it was independent of the membrane attack complex formed by C9. Consistently, complement components were deposited at the surfaces of viral particles with no detectable virolysis. In sera from individuals with severe COVID-19, both complement-mediated neutralization and anti-S2 antibody levels were associated with improved survival. Overall, our data show that complement potentiates the ability of antispike antibodies to neutralize immune-evasive SARS-CoV-2 variants.
M. Jungbauer-Groznica, Pierre Rosenbaum, I. Staropoli et al.· Science Translational Medici...· 0 citations
The utility of the LW25.13 peptide as a scaffold that can be adapted to different virus variants, which may prove useful for the development of peptides against new coronavirus variants of concern in the future, is illustrated.
Nina Raasch, L. Weissenborn, Elie Richel et al.· Journal of Medicinal Chemist...· 0 citations
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