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

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 Murrell () and Gerald M. McInerney ()
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Leo Hanke: Karolinska Institutet
Laura Vidakovics Perez: Karolinska Institutet
Daniel J. Sheward: Karolinska Institutet
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
Ben Murrell: Karolinska Institutet
Gerald M. McInerney: Karolinska Institutet

Nature Communications, 2020, vol. 11, issue 1, 1-9

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-18174-5

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