Téléchargement | - Voir la version finale : Structure-based dual affinity optimization of a SARS-CoV-1/2 cross-reactive single-domain antibody (PDF, 2.0 Mio)
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DOI | Trouver le DOI : https://doi.org/10.1371/journal.pone.0266250 |
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Auteur | Rechercher : Sulea, Traian1Identifiant ORCID : https://orcid.org/0000-0001-5301-8261; Rechercher : Baardsnes, Jason1; Rechercher : Stuible, Matthew1; Rechercher : Rohani, Nazanin1Identifiant ORCID : https://orcid.org/0000-0003-3916-6115; Rechercher : Tran, Anh1Identifiant ORCID : https://orcid.org/0000-0003-0644-6014; Rechercher : Parat, Marie1; Rechercher : Cepero Donates, Yuneivy1; Rechercher : Duchesne, Mélanie1; Rechercher : Plante, Pierre1; Rechercher : Kour, Guneet1; Rechercher : Durocher, Yves1 |
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Éditeur | Rechercher : Silman, Israel1 |
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Affiliation | - Conseil national de recherches du Canada. Thérapeutique en santé humaine
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Format | Texte, Article |
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Résumé | The SARS coronavirus 2 (SARS-CoV-2) spike (S) protein binding to the human ACE2 receptor is the molecular event that initiates viral entry into host cells and leads to infection and virus replication. There is a need for agents blocking viral entry into host cells that are cross-reactive with emerging virus variants. VHH-72 is an anti-SARS-CoV-1 single-domain antibody that also exhibits cross-specificity with SARS-CoV-2 but with decreased binding affinity. Here we applied a structure-based approach to affinity-mature VHH-72 for the SARS-CoV-2 spike protein while retaining the original affinity for SARS-CoV-1. This was achieved by employing the computational platform ADAPT in a constrained dual-affinity optimization mode as a means of broadening specificity. Select mutants designed by ADAPT were formatted as fusions with a human IgG1-Fc fragment. These mutants demonstrated improved binding to the SARS-CoV-2 spike protein due to decreased dissociation rates. Functional testing for virus neutralization revealed improvements relative to the parental VHH72-Fc up to 10-fold using a SARS-CoV-2 pseudotyped lentivirus and 20-fold against the SARS-CoV-2 authentic live virus (Wuhan variant). Binding and neutralization improvements were maintained for some other SARS-CoV-2 variants currently in circulation. These improved VHH-72 mutants are predicted to establish novel interactions with the S antigen. They will be useful, alone or as fusions with other functional modules, in the global quest for treatments of COVID-19 infections. |
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Date de publication | 2022-03-30 |
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Maison d’édition | PLOS |
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Licence | |
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Dans | |
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Langue | anglais |
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Publications évaluées par des pairs | Oui |
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Exporter la notice | Exporter en format RIS |
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Signaler une correction | Signaler une correction (s'ouvre dans un nouvel onglet) |
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Identificateur de l’enregistrement | a3efb377-4bfd-4d4f-9790-564c00013beb |
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Enregistrement créé | 2024-03-19 |
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Enregistrement modifié | 2024-03-19 |
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