| Download | - View final version: Structure-based dual affinity optimization of a SARS-CoV-1/2 cross-reactive single-domain antibody (PDF, 2.0 MiB)
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| DOI | Resolve DOI: https://doi.org/10.1371/journal.pone.0266250 |
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| Author | Search for: Sulea, Traian1ORCID identifier: https://orcid.org/0000-0001-5301-8261; Search for: Baardsnes, Jason1; Search for: Stuible, Matthew1; Search for: Rohani, Nazanin1ORCID identifier: https://orcid.org/0000-0003-3916-6115; Search for: Tran, Anh1ORCID identifier: https://orcid.org/0000-0003-0644-6014; Search for: Parat, Marie1; Search for: Cepero Donates, Yuneivy1; Search for: Duchesne, Mélanie1; Search for: Plante, Pierre1; Search for: Kour, Guneet1; Search for: Durocher, Yves1 |
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| Editor | Search for: Silman, Israel1 |
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| Affiliation | - National Research Council Canada. Human Health Therapeutics
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| Format | Text, Article |
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| Abstract | 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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| Publication date | 2022-03-30 |
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| Publisher | PLOS |
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| Licence | |
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| In | |
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| Language | English |
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| Peer reviewed | Yes |
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| Export citation | Export as RIS |
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| Report a correction | Report a correction (opens in a new tab) |
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| Record identifier | a3efb377-4bfd-4d4f-9790-564c00013beb |
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| Record created | 2024-03-19 |
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| Record modified | 2024-03-19 |
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