Deep Mutational Scanning to Predict Escape from Bebtelovimab in SARS-CoV-2 Omicron Subvariants

Alcantara, Mellissa C.; Higuchi, Yusuke; Kirita, Yuhei; Matoba, Satoaki; Hoshino, Atsushi

doi:10.3390/vaccines11030711

Cited by 12 publications

(8 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Here, we identi ed a total of 40 mutations in the S gene, with 25% (n = 10) of these mutations being speci c to XBB. Among these XBB-speci c mutations, ve have been previously reported to be linked with immune evasion, namely del144 [16], R346T [17,18], V445P [19], F486P [20,21], and F490S [22,23].…”

Section: Discussionmentioning

confidence: 99%

Predominance of the recombinant SARS-CoV-2 lineages XBB in Rio Grande do Sul State, Brazil: a genomic surveillance study and impact on vaccine response

Piccoli,

Castro,

Tessele

et al. 2024

Preprint

View full text Add to dashboard Cite

Purpose The COVID-19 pandemic has been marked by novel viral variants, posing challenges to global public health. Recombination, a viral evolution tool, is implicated in SARS-CoV-2's ongoing evolution. The XBB recombinant lineage, known for evading antibody-mediated immunity, exhibits higher transmissibility without increased disease severity. We investigated the prevalence and genomic features of XBB in SARS-CoV-2-positive cases in Rio Grande do Sul (RS), Brazil. Methods We sequenced 357 samples from epidemiological weeks (EW) 47/2022 to 17/2023, and included 389 publicly available sequences. Clinical and epidemiological data were obtained from DATASUS, e-SUS, and SIVEP GRIPE (data recording systems of the Brazilian Ministry of Health) Results Of these, 143 were classified as XBB and 586 were other Omicron lineages. The BQ.1.1 lineage was most frequent. In March 2023 (EW 10), XBB became dominant, accounting for 83·3% of cases. 97·7% of XBB-infected patients successfully recovered from the infection, with a low mortality rate. Even receiving three vaccine doses and previously infected, 59·5% of the patients experienced reinfection with XBB. However, the interval between XBB infection and the last vaccine dose exceeded a year, potentially causing antibody decline. In addition, we identified 90 mutations in RS circulating XBB, spread throughout the genome, notably in the Spike protein region associated with immune resistance. Conclusion This study provides insights into the dynamics and impact of a recombinant variant becoming predominant for the first time in the state. Continued surveillance of SARS-CoV-2 genomic evolution is crucial for effective public health management.

show abstract

Section: Discussionmentioning

confidence: 99%

Predominance of the recombinant SARS-CoV-2 lineages XBB in Rio Grande do Sul State, Brazil: a genomic surveillance study and impact on vaccine response

Piccoli,

Castro,

Tessele

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…Thus, the use of class 3 antibodies, e.g., bebtelovimab, is with some advantages over the class 1 and class 2 antibodies because (i) the epitope on the RBD surface for class 3 antibodies contains relatively conserved amino acids compared with other regions in the RBM and (ii) the epitope is exposed for mAbs’s binding either at the “closed” or “opened” RBD states . A deep mutational scanning study suggested that mutations at the bebtelovimab binding residues 444–446 and 499–500 resulted in the complete antibody escape found in XBB and BQ.1 variants, which led to the revocation of emergency use authorization for bebtelovimab in the United States and posed further challenges on the development of new vaccines and neutralizing antibodies due to multiple spike protein mutations. − However, as the BA.2, BA.4, and BA.5 omicron subvariants still contained the conserved residues 444–446 and 499–500 outside the heavily mutated regions of RBD, bebtelovimab still displayed its neutralizing efficacy against those subvariants, including the recently emerged BA.2.75.2. ,, …”

Section: Introductionmentioning

confidence: 99%

“…20−22 However, as the BA.2, BA.4, and BA.5 omicron subvariants still contained the conserved residues 444−446 and 499−500 outside the heavily mutated regions of RBD, 23 bebtelovimab still displayed its neutralizing efficacy against those subvariants, including the recently emerged BA.2.75.2. 18,20,24 As the interactions between bebtelovimab and RBD occurred outside of the RBM region for ACE2, the indirect inhibition mechanism should involve protein dynamics and allosteric signals inside the RBD. The concept of allostery for the communication of mechanical signals between different domains within the SARS-CoV-2 spike protein was previously proposed for the development of allosteric drugs that avoid escape mutations through noncompetitive inhibitions.…”

Section: Introductionmentioning

confidence: 99%

Allosteric Signal within the Receptor-Binding Domain of the SARS-CoV-2 Spike Protein Mediated by a Class 3 Monoclonal Antibody Revealed through Molecular Dynamics Simulations and Protein Residue Networks

Boonserm,

Somsoros,

Khunrae

et al. 2024

ACS Omega

View full text Add to dashboard Cite

This study investigated the allosteric action within the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein caused by class 3 monoclonal antibody (mAb) binding. As the emergence of SARS-CoV-2 variants has raised concerns about the effectiveness of treatments by antibodies, targeting the highly conserved class 3 epitopes has become an alternative strategy of antibody design. Simulations of explicitly solvated RBD of the BA.2.75 omicron subvariants were carried out both in the presence and in the absence of bebtelovimab, as a model example of class 3 monoclonal antibodies against the RBD of the SARS-CoV-2 spike protein. The comparative analysis showed that bebtelovimab's binding on two α helices at the epitope region disrupted the nearby interaction network, which triggered a denser interaction network formation on the opposite side of the receptor-binding motif (RBM) region and resulted in a "close" conformation that could prevent the ACE2 binding. A better understanding of this allosteric action could lead to the development of alternative mAbs for further variants of concern. In terms of computational techniques, the communicability matrix could serve as a tool to visualize the effects of allostery, as the pairs of amino acids or secondary structures with high communicability could pinpoint the possible sites to transfer the allosteric signal. Additionally, the communicability gain/loss matrix could help elucidate the consequences of allosteric actions, which could be employed along with other allostery quantification techniques in some previous studies.

show abstract

“…For example, an Omicron subvariant, XBB.1.16, also known as Arcturus, has fueled a surge of COVID-19 cases in 2022 8 . Accordingly, none of the available monoclonal antibodies, with emergency use authorization, neutralize omicron and its variants effectively [9][10][11] . Also, development of drug resistance has been observed for antiviral drugs that target either SARS-CoV-2 polymerase (e.g., Remdesivir, Molnupiravir) or protease (e.g.…”

Section: Introductionmentioning

confidence: 99%

Targeting G9a translational mechanism of SARS-CoV-2 pathogenesis for multifaceted therapeutics of COVID-19 and its sequalae

Muneer,

Xie,

Xie

et al. 2024

Preprint

View full text Add to dashboard Cite

By largely unknown mechanism(s), SARS-CoV-2 hijacks the host translation apparatus to promote COVID-19 pathogenesis. We report that the histone methyltransferase G9a noncanonically regulates viral hijacking of the translation machinery to bring about COVID-19 symptoms of hyperinflammation, lymphopenia, and blood coagulation. Chemoproteomic analysis of COVID-19 patient peripheral mononuclear blood cells (PBMC) identified enhanced interactions between SARS-CoV-2-upregulated G9a and distinct translation regulators, particularly the N6-methyladenosine (m6A) RNA methylase METTL3. These interactions with translation regulators implicated G9a in translational regulation of COVID-19. Inhibition of G9a activity suppressed SARS-CoV-2 replication in human alveolar epithelial cells. Accordingly, multi-omics analysis of the same alveolar cells identified SARS-CoV-2-induced changes at the transcriptional, m6A-epitranscriptional, translational, and post-translational (phosphorylation or secretion) levels that were reversed by inhibitor treatment. As suggested by the aforesaid chemoproteomic analysis, these multi-omics-correlated changes revealed a G9a-regulated translational mechanism of COVID-19 pathogenesis in which G9a directs translation of viral and host proteins associated with SARS-CoV-2 replication and with dysregulation of host response. Comparison of proteomic analyses of G9a inhibitor-treated, SARS-CoV-2 infected cells, or ex vivo culture of patient PBMCs, with COVID-19 patient data revealed that G9a inhibition reversed the patient proteomic landscape that correlated with COVID-19 pathology/symptoms. These data also indicated that the G9a-regulated, inhibitor-reversed, translational mechanism outperformed G9a-transcriptional suppression to ultimately determine COVID-19 pathogenesis and to define the inhibitor action, from which biomarkers of serve symptom vulnerability were mechanistically derived. This cell line-to-patient conservation of G9a-translated, COVID-19 proteome suggests that G9a inhibitors can be used to treat patients with COVID-19, particularly patients with long-lasting COVID-19 sequelae.

show abstract

Deep Mutational Scanning to Predict Escape from Bebtelovimab in SARS-CoV-2 Omicron Subvariants

Cited by 12 publications

References 23 publications

Predominance of the recombinant SARS-CoV-2 lineages XBB in Rio Grande do Sul State, Brazil: a genomic surveillance study and impact on vaccine response

Predominance of the recombinant SARS-CoV-2 lineages XBB in Rio Grande do Sul State, Brazil: a genomic surveillance study and impact on vaccine response

Allosteric Signal within the Receptor-Binding Domain of the SARS-CoV-2 Spike Protein Mediated by a Class 3 Monoclonal Antibody Revealed through Molecular Dynamics Simulations and Protein Residue Networks

Targeting G9a translational mechanism of SARS-CoV-2 pathogenesis for multifaceted therapeutics of COVID-19 and its sequalae

Contact Info

Product

Resources

About