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

Author

Listed:
  • 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
    Medical College of Wisconsin)

  • Joseph P. Gallant

    (University of Wisconsin School of Medicine and Public Health
    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
    University of Wisconsin School of Medicine and Public Health)

  • Jonathan S. Marchant

    (Medical College of Wisconsin)

  • Tyler D. Bold

    (University of Minnesota Medical School
    University of Minnesota)

  • Ryan A. Langlois

    (University of Minnesota
    University of Minnesota)

  • William E. Matchett

    (University of Minnesota
    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
    University of Aberdeen)

  • Hideki Aihara

    (University of Minnesota)

  • Aaron M. LeBeau

    (University of Wisconsin School of Medicine and Public Health
    University of Wisconsin School of Medicine and Public Health
    University of Wisconsin-Madison)

  • Caroline J. Barelle

    (Elasmogen Ltd)

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.

Suggested Citation

  • 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. , 2021. "Mechanisms of SARS-CoV-2 neutralization by shark variable new antigen receptors elucidated through X-ray crystallography," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27611-y
    DOI: 10.1038/s41467-021-27611-y
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    Cited by:

    1. Wei-Hung Chen & Agnes Hajduczki & Elizabeth J. Martinez & Hongjun Bai & Hanover Matz & Thomas M. Hill & Eric Lewitus & William C. Chang & Layla Dawit & Caroline E. Peterson & Phyllis A. Rees & Adelola, 2023. "Shark nanobodies with potent SARS-CoV-2 neutralizing activity and broad sarbecovirus reactivity," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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