Mechanisms of SARS-CoV-2 neutralization by shark variable new antigen receptors elucidated through X-ray crystallography

Obinna C. Ubah, Eric W. Lake, Gihan S. Gunaratne, Joseph P. Gallant, Marie Fernie, Austin J. Robertson, Jonathan S. Marchant, Tyler D. Bold, Ryan A. Langlois, William E. Matchett, Joshua M. Thiede, Ke Shi, Lulu Yin, Nicholas H. Moeller, Surajit Banerjee, Laura Ferguson, Marina Kovaleva, Andrew J. Porter, Hideki Aihara (), Aaron M. LeBeau () and Caroline J. Barelle ()
Additional contact information
Obinna C. Ubah: Elasmogen Ltd
Eric W. Lake: University of Wisconsin School of Medicine and Public Health
Gihan S. Gunaratne: University of Wisconsin School of Medicine and Public Health
Joseph P. Gallant: University of Wisconsin School of Medicine and Public Health
Marie Fernie: Elasmogen Ltd
Austin J. Robertson: University of Wisconsin School of Medicine and Public Health
Jonathan S. Marchant: Medical College of Wisconsin
Tyler D. Bold: University of Minnesota Medical School
Ryan A. Langlois: University of Minnesota
William E. Matchett: University of Minnesota
Joshua M. Thiede: University of Minnesota Medical School
Ke Shi: University of Minnesota
Lulu Yin: University of Minnesota
Nicholas H. Moeller: University of Minnesota
Surajit Banerjee: Cornell University, Advanced Photon Source
Laura Ferguson: Elasmogen Ltd
Marina Kovaleva: Elasmogen Ltd
Andrew J. Porter: Elasmogen Ltd
Hideki Aihara: University of Minnesota
Aaron M. LeBeau: University of Wisconsin School of Medicine and Public Health
Caroline J. Barelle: Elasmogen Ltd

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: Abstract Single-domain Variable New Antigen Receptors (VNARs) from the immune system of sharks are the smallest naturally occurring binding domains found in nature. Possessing flexible paratopes that can recognize protein motifs inaccessible to classical antibodies, VNARs have yet to be exploited for the development of SARS-CoV-2 therapeutics. Here, we detail the identification of a series of VNARs from a VNAR phage display library screened against the SARS-CoV-2 receptor binding domain (RBD). The ability of the VNARs to neutralize pseudotype and authentic live SARS-CoV-2 virus rivalled or exceeded that of full-length immunoglobulins and other single-domain antibodies. Crystallographic analysis of two VNARs found that they recognized separate epitopes on the RBD and had distinctly different mechanisms of virus neutralization unique to VNARs. Structural and biochemical data suggest that VNARs would be effective therapeutic agents against emerging SARS-CoV-2 mutants, including the Delta variant, and coronaviruses across multiple phylogenetic lineages. This study highlights the utility of VNARs as effective therapeutics against coronaviruses and may serve as a critical milestone for nearing a paradigm shift of the greater biologic landscape.

Date: 2021
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DOI: 10.1038/s41467-021-27611-y

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