Broad neutralization of SARS-CoV-2 variants by an inhalable bispecific single-domain antibody

Li, Cheng; Zhan, Wuqiang; Yang, Zhenlin; Tu, Chao; Hu, Gaowei; Zhang, Xiang; Song, Wenping; Du, Shujuan; Zhu, Yuanfei; Huang, Keke; Yu, Ker‐Wei; Zhang, Meng; Mao, Qiyu; Gu, Xiaodan; Zhang, Yi; Xie, Youhua; Deng, Qiang; Song, Yuanlin; Chen, Zhenguo; Lu, Lu; Jiang, Shibo; Wu, Yanling; Sun, Lei; Ying, Tianlei

doi:10.1016/j.cell.2022.03.009

Cited by 91 publications

(100 citation statements)

References 40 publications

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“…Previously, we have demonstrated that nanobodies, when in divalent forms, can protect hamsters from viral infection and lift symptoms (Li et al, 2021a ). This observation was corroborated by several other studies (Huo et al, 2021 ; Nambulli et al, 2021 ; Pymm et al, 2021 ; Ye et al, 2021 ; Li et al, 2022 ). Such previous results warrant a more thorough investigation of the therapeutic potential of DL28 in the future.…”

Section: Discussionsupporting

confidence: 84%

Structural Characterization of a Neutralizing Nanobody With Broad Activity Against SARS-CoV-2 Variants

Zhou

Luo

et al. 2022

Front. Microbiol.

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SARS-CoV-2 and its variants, such as the Omicron continue to threaten public health. The virus recognizes the host cell by attaching its Spike (S) receptor-binding domain (RBD) to the host receptor, ACE2. Therefore, RBD is a primary target for neutralizing antibodies and vaccines. Here, we report the isolation and biological and structural characterization of a single-chain antibody (nanobody) from RBD-immunized alpaca. The nanobody, named DL28, binds to RBD tightly with a KD of 1.56 nM and neutralizes the original SARS-CoV-2 strain with an IC50 of 0.41 μg mL−1. Neutralization assays with a panel of variants of concern (VOCs) reveal its wide-spectrum activity with IC50 values ranging from 0.35 to 1.66 μg mL−1 for the Alpha/Beta/Gamma/Delta and an IC50 of 0.66 μg mL−1 for the currently prevalent Omicron. Competition binding assays show that DL28 blocks ACE2-binding. However, structural characterizations and mutagenesis suggest that unlike most antibodies, the blockage by DL28 does not involve direct competition or steric hindrance. Rather, DL28 may use a “conformation competition” mechanism where it excludes ACE2 by keeping an RBD loop in a conformation incompatible with ACE2-binding.

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Section: Discussionsupporting

confidence: 84%

Structural Characterization of a Neutralizing Nanobody With Broad Activity Against SARS-CoV-2 Variants

Zhou

Luo

et al. 2022

Front. Microbiol.

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“…The most recent study reported that a novel circRNA vaccine showed robust protection against SARS-CoV-2 infection in a mouse model and rhesus macaques. In this study, the researchers also found the circRNARBD-Delta vaccine showed a protective effect not only from the Delta mutation but also against the Omicron variant, which provides an advantage over the circRNARBD-Omicron vaccine that is only effective on the Omicron variant [ 86 ]. These results provide an optimistic insight into further investigation of the circRNA vaccine against virus infection.…”

Section: Vaccine Approach To Prevent Infectionmentioning

confidence: 99%

“…In addition, due to its small size, bn03 was able to bind to the most conserved cryptic epitopes in the deeper binding site. Moreover, the team verified that inhalation is the best method for bn03 delivery compared with other delivery paths [ 86 ]. Although there are some limitations such as limited sample numbers, this well-designed study still provides us positive inspiration for using a similar approach to engineer antibodies for virus treatment.…”

Section: Antiviral Antibodiesmentioning

confidence: 99%

Newly Emerged Antiviral Strategies for SARS-CoV-2: From Deciphering Viral Protein Structural Function to the Development of Vaccines, Antibodies, and Small Molecules

Zhang

Yang

2022

IJMS

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Coronavirus disease 2019 (COVID-19) caused by the infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become the most severe health crisis, causing extraordinary economic disruption worldwide. SARS-CoV-2 is a single-stranded RNA-enveloped virus. The process of viral replication and particle packaging is finished in host cells. Viral proteins, including both structural and nonstructural proteins, play important roles in the viral life cycle, which also provides the targets of treatment. Therefore, a better understanding of the structural function of virus proteins is crucial to speed up the development of vaccines and therapeutic strategies. Currently, the structure and function of proteins encoded by the SARS-CoV-2 genome are reviewed by several studies. However, most of them are based on the analysis of SARS-CoV-1 particles, lacking a systematic review update for SARS-CoV-2. Here, we specifically focus on the structure and function of proteins encoded by SARS-CoV-2. Viral proteins that contribute to COVID-19 infection and disease pathogenesis are reviewed according to the most recent research findings. The structure-function correlation of viral proteins provides a fundamental rationale for vaccine development and targeted therapy. Then, current antiviral vaccines are updated, such as inactive viral vaccines and protein-based vaccines and DNA, mRNA, and circular RNA vaccines. A summary of other therapeutic options is also reviewed, including monoclonal antibodies such as a cross-neutralizer antibody, a constructed cobinding antibody, a dual functional monoclonal antibody, an antibody cocktail, and an engineered bispecific antibody, as well as peptide-based inhibitors, chemical compounds, and clustered regularly interspaced short palindromic repeats (CRISPR) exploration. Overall, viral proteins and their functions provide the basis for targeted therapy and vaccine development.

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“…Structural basis for potent antibody neutralization of the Omicron variant was examined in an illuminating investigation in which multiple cryo-EM structures of antibodies bound to the S Omicron protein were revealed. 64 This study provided a systematic structural analysis of several major classes of antibodies revealing potential mechanisms of antibody neutralization, escape and retained potency. This study showed that in the context of S trimers, Omicron mutations provide only a moderate alteration in binding affinity to ACE2, showing that affinity improving changes are used to compensate for mutations required for immune escape.…”

Section: Introductionmentioning

confidence: 99%

“…This structural study claimed that variant evolution may be driven not by the optimization of ACE2 binding but primarily by immune pressure. 64 The cryo-EM studies identified recently two highly conserved regions on the Omicron variant RBD, including a part of the lateral surface and the cryptic site inside the trimeric interface, recognized by broadly neutralizing antibodies. 65 A bispecific single-domain antibody was designed to simultaneously and synergistically bind these two regions as revealed by cryo-EM structures and showing that this bispecific antibody can exhibit significant neutralization breadth and therapeutic efficacy in mouse models of SARS-CoV-2 infections.…”

Section: Introductionmentioning

confidence: 99%

Hierarchical Computational Modeling and Dynamic Network Analysis of Allosteric Regulation in the SARS-CoV-2 Spike Omicron Trimer Structures: Omicron Mutations Cooperate to Allosterically Control Balance of Protein Stability and Conformational Adaptability

Verkhivker

Agajanian

Kassab

et al. 2022

Preprint

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Structural and computational studies of the Omicron spike protein in various functional states and complexes provided important insights into molecular mechanisms underlying binding, high transmissibility, and escaping immune defense. However, the regulatory roles and functional coordination of the Omicron mutations are poorly understood and often ignored in the proposed mechanisms. In this work, we explored the hypothesis that the SARS-CoV-2 spike protein can function as a robust allosterically regulated machinery in which Omicron mutational sites are dynamically coupled and form a central engine of the allosteric network that regulates the balance between conformational plasticity, protein stability, and functional adaptability. In this study, we employed coarse-grained dynamics simulations of multiple full-length SARS-CoV-2 spike Omicron trimers structures in the closed and open states with the local energetic frustration analysis and collective dynamics mapping to understand the determinants and key hotspots driving the balance of protein stability and conformational adaptability. We have found that the Omicron mutational sites at the inter-protomer regions form regulatory clusters that control functional transitions between the closed and open states. Through perturbation-based modeling of allosteric interaction networks and diffusion analysis of communications in the closed and open spike states, we quantify the allosterically regulated activation mechanism and uncover specific regulatory roles of the Omicron mutations. The network modeling demonstrated that Omicron mutations form the inter-protomer electrostatic bridges that connect local stable communities and function as allosteric switches of signal transmission. The results of this study are consistent with the experiments, revealing distinct and yet complementary role of the Omicron mutational sites as a network of hotspots that enable allosteric modulation of structural stability and conformational changes which are central for spike activation and virus transmissibility.

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Broad neutralization of SARS-CoV-2 variants by an inhalable bispecific single-domain antibody

Cited by 91 publications

References 40 publications

Structural Characterization of a Neutralizing Nanobody With Broad Activity Against SARS-CoV-2 Variants

Structural Characterization of a Neutralizing Nanobody With Broad Activity Against SARS-CoV-2 Variants

Newly Emerged Antiviral Strategies for SARS-CoV-2: From Deciphering Viral Protein Structural Function to the Development of Vaccines, Antibodies, and Small Molecules

Hierarchical Computational Modeling and Dynamic Network Analysis of Allosteric Regulation in the SARS-CoV-2 Spike Omicron Trimer Structures: Omicron Mutations Cooperate to Allosterically Control Balance of Protein Stability and Conformational Adaptability

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