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• W3161356734 abstract "Abstract The respiratory virus responsible for Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-2), has impacted nearly every aspect of life worldwide, claiming the lives of over 2.5 million people globally, at the time of this publication. Neutralizing nanobodies (V H H) represent a promising therapeutic intervention strategy to address the current SARS-2 pandemic and provide a powerful toolkit to address future virus outbreaks. Using a synthetic, high-diversity V H H bacteriophage library, several potent neutralizing V H H antibodies were identified and evaluated for their capacity to tightly bind to the SARS-2 receptor-binding domain (RBD), to prevent binding of SARS-2 spike (S) to the cellular receptor Angiotensin-converting enzyme 2 (ACE2), and to neutralize viral infection. Preliminary preclinical evaluation of multiple nanobody candidates demonstrate that they are prophylactically and therapeutically effective in vivo against wildtype SARS-2. The identified and characterized nanobodies described herein represent viable candidates for further preclinical evaluation and another tool to add to our therapeutic arsenal to address the COVID-19 pandemic. Author Summary To fully address the on-going pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-2), it will be important to have both vaccines and therapeutic strategies to prevent and mitigate the effects of SARS-2. In this study, we describe the identification and characterization of potently neutralizing humanized single domain heavy chain (V H H) antibodies that have binding affinity for both the original Wuhan strain and widely circulating B.1.1.7/UK strain. V H H antibodies have the same therapeutic potential as conventional antibodies in half the size and with greater stability and solubility. Using a synthetic humanized high-diversity V H H phage library we identified several candidates with strong affinity for the SARS-2 spike that block the interaction of SARS-2 spike with the cellular receptor ACE2, and effectively neutralize infection with SARS-2 in vitro . By sequencing viral escape mutants generated in the presence of each V H H we mapped the binding sites of the V H H antibodies and assessed their affinity against newly emerging SARS-2 variants. Finally, we demonstrate that two of these V H H antibodies show prophylactic and therapeutic efficacy in vivo against challenge with SARS-2. This study establishes that screening highly diverse V H H phage libraries against viral threats can yield highly effective therapeutic agents in real time." @default.
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• W3161356734 date "2021-05-06" @default.
• W3161356734 modified "2023-09-25" @default.
• W3161356734 title "Development of Potent and Effective Synthetic SARS-CoV-2 Neutralizing Nanobodies" @default.
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• W3161356734 doi "https://doi.org/10.1101/2021.05.06.442911" @default.
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