Structural insights into the cross-neutralization of SARS-CoV and SARS-CoV-2 by the human monoclonal antibody 47D11

Fédry, Juliette; Hurdiss, Daniel L.; Wang, Chunyan; Li, Wentao; Obal, Gonzalo; Drulyte, Ieva; Du, Wenjuan; Howes, Stuart C.; Kuppeveld, Frank J. M. van; Förster, Friedrich; Bosch, Berend-Jan

doi:10.1126/sciadv.abf5632

Cited by 46 publications

(60 citation statements)

References 103 publications

(166 reference statements)

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“…This Ab was generated from H2L2 human Ab transgenic mice, which were immunized with the S ectodomain of HCoV-OC43, SARS-CoV, and MERS-CoV. Cryo-EM structures showed that 47D11 binds specifically to the closed conformation of the RBD, distal to the ACE2 binding site [ 67 ]. Interestingly, 47D11 preferentially recognizes the partially open conformation of the SARS-CoV-2 S protein, suggesting that it could be used effectively in combination with other Abs that target the exposed RBM.…”

Section: Therapeutic Absmentioning

confidence: 99%

Monoclonal antibodies for COVID-19 therapy and SARS-CoV-2 detection

et al. 2022

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The coronavirus disease 2019 (COVID-19) pandemic is an exceptional public health crisis that demands the timely creation of new therapeutics and viral detection. Owing to their high specificity and reliability, monoclonal antibodies (mAbs) have emerged as powerful tools to treat and detect numerous diseases. Hence, many researchers have begun to urgently develop Ab-based kits for the detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Ab drugs for use as COVID-19 therapeutic agents. The detailed structure of the SARS-CoV-2 spike protein is known, and since this protein is key for viral infection, its receptor-binding domain (RBD) has become a major target for therapeutic Ab development. Because SARS-CoV-2 is an RNA virus with a high mutation rate, especially under the selective pressure of aggressively deployed prophylactic vaccines and neutralizing Abs, the use of Ab cocktails is expected to be an important strategy for effective COVID-19 treatment. Moreover, SARS-CoV-2 infection may stimulate an overactive immune response, resulting in a cytokine storm that drives severe disease progression. Abs to combat cytokine storms have also been under intense development as treatments for COVID-19. In addition to their use as drugs, Abs are currently being utilized in SARS-CoV-2 detection tests, including antigen and immunoglobulin tests. Such Ab-based detection tests are crucial surveillance tools that can be used to prevent the spread of COVID-19. Herein, we highlight some key points regarding mAb-based detection tests and treatments for the COVID-19 pandemic.

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Section: Therapeutic Absmentioning

confidence: 99%

Monoclonal antibodies for COVID-19 therapy and SARS-CoV-2 detection

et al. 2022

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“…Six monoclonal antibodies that cross-reacted with the S proteins of SARS-CoV, SARS-CoV-2, and other coronaviruses via diverse epitopes were identified [ 91 ]. Human monoclonal antibody (mAb) 47D11 can specifically recognize the downward conformation of the viral RBD by targeting the conserved hydrophobic pocket in the RBD of SARS-CoV and SARS-CoV-2, and thus capturing these two viruses in a completely closed and a partially open conformation, respectively [ 92 ]. The neutralization efficiency of 47D11 is not affected by the mutations in the RBM (receptor binding motif), such as K417N, E484K, or N501Y, which makes 47D11 a promising therapeutic candidate against the new and rapidly spreading SARS-CoV-2 and its variants [ 92 ].…”

Section: Targets For Pan-coronavirus Vaccinesmentioning

confidence: 99%

“…Human monoclonal antibody (mAb) 47D11 can specifically recognize the downward conformation of the viral RBD by targeting the conserved hydrophobic pocket in the RBD of SARS-CoV and SARS-CoV-2, and thus capturing these two viruses in a completely closed and a partially open conformation, respectively [ 92 ]. The neutralization efficiency of 47D11 is not affected by the mutations in the RBM (receptor binding motif), such as K417N, E484K, or N501Y, which makes 47D11 a promising therapeutic candidate against the new and rapidly spreading SARS-CoV-2 and its variants [ 92 ]. Further research shows that 47D11 can effectively neutralize ACE2-dependent betacoronaviruses, such as SARS-CoV, SARS-CoV-2, and the SARS-like bat betacoronavirus, WIV16 [ 92 ].…”

Section: Targets For Pan-coronavirus Vaccinesmentioning

confidence: 99%

“…The neutralization efficiency of 47D11 is not affected by the mutations in the RBM (receptor binding motif), such as K417N, E484K, or N501Y, which makes 47D11 a promising therapeutic candidate against the new and rapidly spreading SARS-CoV-2 and its variants [ 92 ]. Further research shows that 47D11 can effectively neutralize ACE2-dependent betacoronaviruses, such as SARS-CoV, SARS-CoV-2, and the SARS-like bat betacoronavirus, WIV16 [ 92 ]. RBD trimer adjuvanted with Alum-3M-052 can induce effective neutralizing antibodies and protect mice and rhesus monkeys from SARS-CoV-2 infection [ 93 ].…”

Section: Targets For Pan-coronavirus Vaccinesmentioning

confidence: 99%

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Possible Targets of Pan-Coronavirus Antiviral Strategies for Emerging or Re-Emerging Coronaviruses

Zhang

Chen

et al. 2021

Microorganisms

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Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), which caused Coronaviruses Disease 2019 (COVID-19) and a worldwide pandemic, is the seventh human coronavirus that has been cross-transmitted from animals to humans. It can be predicted that with continuous contact between humans and animals, more viruses will spread from animals to humans. Therefore, it is imperative to develop universal coronavirus or pan-coronavirus vaccines or drugs against the next coronavirus pandemic. However, a suitable target is critical for developing pan-coronavirus antivirals against emerging or re-emerging coronaviruses. In this review, we discuss the latest progress of possible targets of pan-coronavirus antiviral strategies for emerging or re-emerging coronaviruses, including targets for pan-coronavirus inhibitors and vaccines, which will provide prospects for the current and future research and treatment of the disease.

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“…Further, to set an appropriate baseline for the Spike-Furin interaction in SARS-CoV-2, a second round of docking was performed by taking the same ligand (Furin: 1P8J) and docking it onto the representative homologous Spike structure (PDB ID: 7AKJ) [58] of SARS-CoV (2002. This cryo EM structure was solved in the process of exploring 'the convalescent patient sera option' for the then seemed possible prevention and treatment of COVID-19, as a natural extension of SARS [59].…”

Section: Details and Rationales Of Experimental Structural Templates Used For Docking And Dynamicsmentioning

confidence: 99%

Capturing a crucial ‘disorder-to-order transition’ at the heart of the coronavirus molecular pathology – triggered by highly persistent, interchangeable salt-bridges

Roy

Ghosh²,

Bandyapadhyay

et al. 2021

Preprint

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The COVID-19 origin debate has greatly been influenced by Genome comparison studies of late, revealing the seemingly sudden emergence of the Furin-Like Cleavage Site at the S1/S2 junction of the SARS-CoV-2 Spike (FLCS_Spike) containing its 681_PRRAR_685 motif, absent in other related respiratory viruses. Being the rate-limiting (i.e., the slowest) step, the host Furin cleavage is instrumental in the abrupt increase in transmissibility in COVID-19, compared to earlier onsets of respiratory viral diseases. In such a context, the current paper entraps a disorder-to-order transition of the FLCS_Spike (concomitant to an entropy arrest) upon binding to Furin. The interaction clearly seems to be optimized for a more efficient proteolytic cleavage in SARS-CoV-2. The study further shows the formation of dynamically interchangeable and persistent networks of salt-bridges at the Spike-Furin interface in SARS-CoV-2 involving the three arginines (R682, R683, R685) of the FLCS_Spike with several anionic residues (E230, E236, D259, D264, D306) coming from Furin, strategically distributed around its catalytic triad. Multiplicity and structural degeneracy of plausible salt-bridge network archetypes seems the other key characteristic features of the Spike-Furin binding in SARS-CoV-2 allowing the system to breathe - a trademark of protein disorder transitions. Interestingly, with respect to the homologous interaction in SARS-CoV (2002/2003) taken as a baseline, the Spike-Furin binding events generally in the coronavirus lineage seems to have a preference for ionic bond formation, even with lesser number of cationic residues at their potentially polybasic FLCS_Spike patches. The interaction energies are suggestive of a characteristic metastabilities attributed to Spike-Furin interactions generally to the coronavirus lineage - which appears to be favorable for proteolytic cleavages targeted at flexible protein loops. The current findings not only offer novel mechanistic insights into the coronavirus molecular pathology and evolution but also add substantially to the existing theories of proteolytic cleavages.

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Structural insights into the cross-neutralization of SARS-CoV and SARS-CoV-2 by the human monoclonal antibody 47D11

Cited by 46 publications

References 103 publications

Monoclonal antibodies for COVID-19 therapy and SARS-CoV-2 detection

Monoclonal antibodies for COVID-19 therapy and SARS-CoV-2 detection

Possible Targets of Pan-Coronavirus Antiviral Strategies for Emerging or Re-Emerging Coronaviruses

Capturing a crucial ‘disorder-to-order transition’ at the heart of the coronavirus molecular pathology – triggered by highly persistent, interchangeable salt-bridges

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