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Mechanisms of SARS-CoV-2 neutralization by shark variable new antigen receptors elucidated through X-ray crystallography.
Ubah, Obinna C; Lake, Eric W; Gunaratne, Gihan S; Gallant, Joseph P; Fernie, Marie; Robertson, Austin J; Marchant, Jonathan S; Bold, Tyler D; Langlois, Ryan A; Matchett, William E; Thiede, Joshua M; Shi, Ke; Yin, Lulu; Moeller, Nicholas H; Banerjee, Surajit; Ferguson, Laura; Kovaleva, Marina; Porter, Andrew J; Aihara, Hideki; LeBeau, Aaron M; Barelle, Caroline J.
  • Ubah OC; Elasmogen Ltd, Liberty Building Foresterhill Road, Aberdeen, AB25 2ZP, UK.
  • Lake EW; Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, 53705, USA.
  • Gunaratne GS; Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, 53705, USA.
  • Gallant JP; Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.
  • Fernie M; Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, 53705, USA.
  • Robertson AJ; Molecular and Cellular Pharmacology Training Program, University of Wisconsin School of Medicine and Public Health, Madison, WI, 53705, USA.
  • Marchant JS; Elasmogen Ltd, Liberty Building Foresterhill Road, Aberdeen, AB25 2ZP, UK.
  • Bold TD; Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, 53705, USA.
  • Langlois RA; Molecular and Cellular Pharmacology Training Program, University of Wisconsin School of Medicine and Public Health, Madison, WI, 53705, USA.
  • Matchett WE; Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.
  • Thiede JM; Division of Infectious Diseases and International Medicine, University of Minnesota Medical School, Minneapolis, MN, 55455, USA.
  • Shi K; Center for Immunology, University of Minnesota, Minneapolis, MN, 55455, USA.
  • Yin L; Center for Immunology, University of Minnesota, Minneapolis, MN, 55455, USA.
  • Moeller NH; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN, 55455, USA.
  • Banerjee S; Center for Immunology, University of Minnesota, Minneapolis, MN, 55455, USA.
  • Ferguson L; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN, 55455, USA.
  • Kovaleva M; Division of Infectious Diseases and International Medicine, University of Minnesota Medical School, Minneapolis, MN, 55455, USA.
  • Porter AJ; Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN, 55455, USA.
  • Aihara H; Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN, 55455, USA.
  • LeBeau AM; Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN, 55455, USA.
  • Barelle CJ; Northeastern Collaborative Access Team, Cornell University, Advanced Photon Source, Lemont, IL, 60439, USA.
Nat Commun ; 12(1): 7325, 2021 12 16.
Article in English | MEDLINE | ID: covidwho-1585854
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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Sharks / Receptors, Antigen / Crystallography, X-Ray / Antibodies, Neutralizing / Antibodies, Viral Type of study: Randomized controlled trials Topics: Variants Limits: Animals Language: English Journal: Nat Commun Journal subject: Biology / Science Year: 2021 Document Type: Article Affiliation country: S41467-021-27611-y

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Sharks / Receptors, Antigen / Crystallography, X-Ray / Antibodies, Neutralizing / Antibodies, Viral Type of study: Randomized controlled trials Topics: Variants Limits: Animals Language: English Journal: Nat Commun Journal subject: Biology / Science Year: 2021 Document Type: Article Affiliation country: S41467-021-27611-y