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Bebtelovimab-bound SARS-CoV-2 RBD mutants: resistance profiling and validation with escape mutations, clinical results, and viral genome sequences.
Bhagat, Khushboo; Maurya, Shweata; Yadav, Amar Jeet; Tripathi, Timir; Padhi, Aditya K.
Afiliação
  • Bhagat K; Laboratory for Computational Biology & Biomolecular Design, School of Biochemical Engineering, Indian Institute of Technology (BHU) Varanasi, Varanasi, India.
  • Maurya S; Laboratory for Computational Biology & Biomolecular Design, School of Biochemical Engineering, Indian Institute of Technology (BHU) Varanasi, Varanasi, India.
  • Yadav AJ; Laboratory for Computational Biology & Biomolecular Design, School of Biochemical Engineering, Indian Institute of Technology (BHU) Varanasi, Varanasi, India.
  • Tripathi T; Molecular and Structural Biophysics Laboratory, Department of Zoology, North-Eastern Hill University, Shillong, India.
  • Padhi AK; Laboratory for Computational Biology & Biomolecular Design, School of Biochemical Engineering, Indian Institute of Technology (BHU) Varanasi, Varanasi, India.
FEBS Lett ; 598(19): 2394-2416, 2024 Oct.
Article em En | MEDLINE | ID: mdl-39107909
ABSTRACT
The dynamic evolution of SARS-CoV-2 variants necessitates ongoing advancements in therapeutic strategies. Despite the promise of monoclonal antibody (mAb) therapies like bebtelovimab, concerns persist regarding resistance mutations, particularly single-to-multipoint mutations in the receptor-binding domain (RBD). Our study addresses this by employing interface-guided computational protein design to predict potential bebtelovimab-resistance mutations. Through extensive physicochemical analysis, mutational preferences, precision-recall metrics, protein-protein docking, and energetic analyses, combined with all-atom, and coarse-grained molecular dynamics (MD) simulations, we elucidated the structural-dynamics-binding features of the bebtelovimab-RBD complexes. Identification of susceptible RBD residues under positive selection pressure, coupled with validation against bebtelovimab-escape mutations, clinically reported resistance mutations, and viral genomic sequences enhances the translational significance of our findings and contributes to a better understanding of the resistance mechanisms of SARS-CoV-2.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Genoma Viral / Simulação de Dinâmica Molecular / Glicoproteína da Espícula de Coronavírus / SARS-CoV-2 / COVID-19 / Tratamento Farmacológico da COVID-19 / Mutação Limite: Humans Idioma: En Revista: FEBS Lett Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Genoma Viral / Simulação de Dinâmica Molecular / Glicoproteína da Espícula de Coronavírus / SARS-CoV-2 / COVID-19 / Tratamento Farmacológico da COVID-19 / Mutação Limite: Humans Idioma: En Revista: FEBS Lett Ano de publicação: 2024 Tipo de documento: Article