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An alpaca nanobody neutralizes SARS-CoV-2 by blocking receptor interaction

Author

Listed:
  • Leo Hanke

    (Karolinska Institutet)

  • Laura Vidakovics Perez

    (Karolinska Institutet)

  • Daniel J. Sheward

    (Karolinska Institutet
    University of Cape Town)

  • Hrishikesh Das

    (Karolinska Institutet)

  • Tim Schulte

    (Karolinska University Hospital)

  • Ainhoa Moliner-Morro

    (Karolinska Institutet)

  • Martin Corcoran

    (Karolinska Institutet)

  • Adnane Achour

    (Karolinska University Hospital)

  • Gunilla B. Karlsson Hedestam

    (Karolinska Institutet)

  • B. Martin Hällberg

    (Karolinska Institutet
    Centre for Structural Systems Biology)

  • Ben Murrell

    (Karolinska Institutet)

  • Gerald M. McInerney

    (Karolinska Institutet)

Abstract

SARS-CoV-2 enters host cells through an interaction between the spike glycoprotein and the angiotensin converting enzyme 2 (ACE2) receptor. Directly preventing this interaction presents an attractive possibility for suppressing SARS-CoV-2 replication. Here, we report the isolation and characterization of an alpaca-derived single domain antibody fragment, Ty1, that specifically targets the receptor binding domain (RBD) of the SARS-CoV-2 spike, directly preventing ACE2 engagement. Ty1 binds the RBD with high affinity, occluding ACE2. A cryo-electron microscopy structure of the bound complex at 2.9 Å resolution reveals that Ty1 binds to an epitope on the RBD accessible in both the ‘up’ and ‘down’ conformations, sterically hindering RBD-ACE2 binding. While fusion to an Fc domain renders Ty1 extremely potent, Ty1 neutralizes SARS-CoV-2 spike pseudovirus as a 12.8 kDa nanobody, which can be expressed in high quantities in bacteria, presenting opportunities for manufacturing at scale. Ty1 is therefore an excellent candidate as an intervention against COVID-19.

Suggested Citation

  • Leo Hanke & Laura Vidakovics Perez & Daniel J. Sheward & Hrishikesh Das & Tim Schulte & Ainhoa Moliner-Morro & Martin Corcoran & Adnane Achour & Gunilla B. Karlsson Hedestam & B. Martin Hällberg & Ben, 2020. "An alpaca nanobody neutralizes SARS-CoV-2 by blocking receptor interaction," Nature Communications, Nature, vol. 11(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-18174-5
    DOI: 10.1038/s41467-020-18174-5
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    Cited by:

    1. Mingxi Li & Yifei Ren & Zhen Qin Aw & Bo Chen & Ziqing Yang & Yuqing Lei & Lin Cheng & Qingtai Liang & Junxian Hong & Yiling Yang & Jing Chen & Yi Hao Wong & Jing Wei & Sisi Shan & Senyan Zhang & Jiwa, 2022. "Broadly neutralizing and protective nanobodies against SARS-CoV-2 Omicron subvariants BA.1, BA.2, and BA.4/5 and diverse sarbecoviruses," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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