Broadly neutralizing antibodies target the coronavirus fusion peptide

Dacon, Cherrelle; Tucker, Courtney; Peng, Linghang; Lee, Chang-Chun David; Lin, Ting-Hui; Yuan, Meng; Yu, Cong; Wang, Lingshu; Purser, Lauren; Williams, Jazmean K.; Pyo, Chul‐Woo; Košík, Ivan; Hu, Zhe; Zhao, Ming; Mohan, Divya; Cooper, Andrew J.; Peterson, Mary; Skinner, Jeff; Dixit, Saurabh; Kollins, Erin; Huzella, Louis; Perry, Donna L.; Byrum, Russell; Lembirik, Sanae; Drawbaugh, David; Eaton, Brett; Zhang, Yi; Yang, Eun Sung; Chen, Man; Leung, Kwanyee; Weinberg, Rona Singer; Pegu, Amarendra; Geraghty, Daniel E.; Davidson, Edgar; Douagi, Iyadh; Moir, Susan; Yewdell, Jonathan W.; Schmaljohn, Connie S.; Crompton, Peter D.; Holbrook, Michael R.; Nemazee, David; Mascola, John R.; Wilson, Ian A.; Tan, Joshua

doi:10.1126/science.abq3773

Cited by 155 publications

(203 citation statements)

References 75 publications

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“…Apart from the SH region mentioned earlier, S2 FPs are also highly conserved among all coronavirus genera, suggesting that broad-spectrum antibodies could be found by targeting this epitope 86 – 88 . Some recently identified antibodies to this epitope have excellent broadly neutralizing activity against alpha-CoVs, beta-CoVs and even some gamma-CoVs and delta-CoVs 86 , 87 . For example, COV44-62 and COV44-79, which were both isolated from patients recovering from COVID-19, can bind the S2 FP region through recognition of the ‘RSFIEDLLF’ motif.…”

Section: The S2 Fpsmentioning

confidence: 80%

“…For example, COV44-62 and COV44-79, which were both isolated from patients recovering from COVID-19, can bind the S2 FP region through recognition of the ‘RSFIEDLLF’ motif. Interestingly, these antibodies do not compete with S2P6, the aforementioned S2 SH-targeting antibody, for binding to the SARS-CoV-2 S protein 86 , suggesting the possibility of combining S2 SH and S2 FP recognition in a bispecific antibody. Crystal structure analysis revealed that COV44-62 interacts with S2, that spans residues 814–824, mainly through hydrogen bonds, salt bridges and hydrophobic interactions within HCDR1, HCDR2, HCDR3, LCDR1 and LCDR3.…”

Section: The S2 Fpsmentioning

confidence: 99%

“…Similarly, COV44-79 utilizes HCDR1, HCDR2, HCDR3 and LCDR3 to bind SARS-CoV-2 and interacts with S2 residues 812–823 (ref. 86 ). Of note, both antibodies broadly neutralize beta-CoVs, but show some differences in activity against MERS-CoV.…”

Section: The S2 Fpsmentioning

confidence: 99%

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Broadly neutralizing antibodies to SARS-CoV-2 and other human coronaviruses

et al. 2022

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a recently emerged pathogenic human coronavirus that belongs to the sarbecovirus lineage of the genus Betacoronavirus. The ancestor strain has evolved into a number of variants of concern, with the Omicron variant of concern now having many distinct sublineages. The ongoing COVID-19 pandemic caused by SARS-CoV-2 has caused serious damage to public health and the global economy, and one strategy to combat COVID-19 has been the development of broadly neutralizing antibodies for prophylactic and therapeutic use. Many are in preclinical and clinical development, and a few have been approved for emergency use. Here we summarize neutralizing antibodies that target four key regions within the SARS-CoV-2 spike (S) protein, namely the N-terminal domain and the receptor-binding domain in the S1 subunit, and the stem helix region and the fusion peptide region in the S2 subunit. Understanding the characteristics of these broadly neutralizing antibodies will accelerate the development of new antibody therapeutics and provide guidance for the rational design of next-generation vaccines.

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Section: The S2 Fpsmentioning

confidence: 80%

Section: The S2 Fpsmentioning

confidence: 99%

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Broadly neutralizing antibodies to SARS-CoV-2 and other human coronaviruses

et al. 2022

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“…Antibodies targeting the fusion peptide could block either protease cleavage or insertion of cleaved fusion peptide into host membrane. Interestingly, recent studies have revealed that some antibodies do indeed target the fusion peptide and contribute to SARS‐CoV‐2 neutralization 242,243,248 …”

Section: Neutralizing Epitopes On Sars‐cov‐2 Spikementioning

confidence: 99%

Protective neutralizing epitopes in SARS‐CoV‐2

Liu

Wilson

2022

Immunological Reviews

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The COVID‐19 pandemic has caused an unprecedented health crisis and economic burden worldwide. Its etiological agent SARS‐CoV‐2, a new virus in the coronavirus family, has infected hundreds of millions of people worldwide. SARS‐CoV‐2 has evolved over the past 2 years to increase its transmissibility as well as to evade the immunity established by previous infection and vaccination. Nevertheless, strong immune responses can be elicited by viral infection and vaccination, which have proved to be protective against the emergence of variants, particularly with respect to hospitalization or severe disease. Here, we review our current understanding of how the virus enters the host cell and how our immune system is able to defend against cell entry and infection. Neutralizing antibodies are a major component of our immune defense and have been extensively studied for SARS‐CoV‐2 and its variants. Structures of these neutralizing antibodies have provided valuable insights into epitopes that are protective against the original ancestral virus and the variants that have emerged. The molecular characterization of neutralizing epitopes as well as epitope conservation and resistance are important for design of next‐generation vaccines and antibody therapeutics.

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“…These broad sarbecovirus SARS-CoV-2 NAbs (bsNAbs) have epitopes located on sarbecovirus conserved regions, and people believe that they would not be easily escaped by SARS-CoV-2 variants. Various bsNAbs targeting spike protein's RBD or S2 region have been discovered [24][25][26][27] . S2-targeting bsNAbs indeed displayed exceptional SARS-CoV-2 neutralization breadth, but their potency is rather low for NAb drug development.…”

Section: Mainmentioning

confidence: 99%

Rational identification of potent and broad sarbecovirus-neutralizing antibody cocktails from SARS convalescents

Cao

Jian

Zhang

et al. 2022

Preprint

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SARS-CoV-2 Omicron sublineages have escaped most RBD-targeting therapeutic neutralizing antibodies (NAbs), which proves the previous NAb drug screening strategies deficient against the fast-evolving SARS-CoV-2. Better broad NAb drug candidate selection methods are needed. Here, we describe a rational approach for identifying RBD-targeting broad SARS-CoV-2 NAb cocktails. Based on high-throughput epitope determination, we propose that broad NAb drugs should target non-immunodominant RBD epitopes to avoid herd immunity-directed escape mutations. Also, their interacting antigen residues should focus on sarbecovirus conserved sites and associate with critical viral functions, making the antibody-escaping mutations less likely to appear. Following the criteria, a featured non-competing antibody cocktail, SA55+SA58, is identified from a large collection of broad sarbecovirus NAbs isolated from SARS convalescents. SA55+SA58 potently neutralizes ACE2-utilizing sarbecoviruses, including circulating Omicron variants, and could serve as broad SARS-CoV-2 prophylactics to offer long-term protection. Our screening strategy can also be further applied to identify broad-spectrum NAb drugs against other fast-evolving viruses.

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Broadly neutralizing antibodies target the coronavirus fusion peptide

Cited by 155 publications

References 75 publications

Broadly neutralizing antibodies to SARS-CoV-2 and other human coronaviruses

Broadly neutralizing antibodies to SARS-CoV-2 and other human coronaviruses

Protective neutralizing epitopes in SARS‐CoV‐2

Rational identification of potent and broad sarbecovirus-neutralizing antibody cocktails from SARS convalescents

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