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

Hanke, L.; Perez Vidakovics, M. L.; Sheward, D.; Das, H.; Schulte, T.; Moliner Morro, A.; Corcoran, M.; Achour, A.; Karlsson Hedestam, G.; Hällberg, B. M.; Murrell, B.; McInerney, G. M.

doi:10.1101/2020.06.02.130161

bioRxiv · 10.1101/2020.06.02.130161

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

Hanke, L.·Perez Vidakovics, M. L.·Sheward, D.·Das, H.·Schulte, T.·Moliner Morro, A.·Corcoran, M.·Achour, A.·Karlsson Hedestam, G.·Hällberg, B. M.·Murrell, B.·McInerney, G. M.

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Abstract

SARS-CoV-2 is the etiologic agent of COVID-19, currently causing a devastating pandemic for which pharmacological interventions are urgently needed. The virus 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. The nanobody binds with high affinity in the low nM range to the RBD, 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 and that Ty1 sterically hinders RBD-ACE2 binding. This 12.8 kDa nanobody does not need an Fc domain to neutralize SARS-CoV-2, and 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.Competing Interest StatementThe authors have declared no competing interest.View Full Text

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Hanke, L., Perez Vidakovics, M. L., Sheward, D., Das, H., Schulte, T., Moliner Morro, A., Corcoran, M., Achour, A., Karlsson Hedestam, G., Hällberg, B. M., Murrell, B., McInerney, G. M.. 2020-06-02. An alpaca nanobody neutralizes SARS-CoV-2 by blocking receptor interaction. https://doi.org/10.1101/2020.06.02.130161

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