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TitleAn alpaca nanobody neutralizes SARS-CoV-2 by blocking receptor interaction.
Journal, issue, pagesNat Commun, Vol. 11, Issue 1, Page 4420, Year 2020
Publish dateSep 4, 2020
AuthorsLeo 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 / Gerald M McInerney /
PubMed AbstractSARS-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 ...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.
External linksNat Commun / PubMed:32887876 / PubMed Central
MethodsEM (single particle)
Resolution2.93 Å
Structure data

EMDB-11526, PDB-6zxn:
Cryo-EM structure of the SARS-CoV-2 spike protein bound to neutralizing nanobodies (Ty1)
Method: EM (single particle) / Resolution: 2.93 Å

EMDB-11728:
SARS-CoV-2 spike glycoprotein bound to nanobodies (Ty1)
Method: EM (single particle) / Resolution: 2.93 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

Source
  • severe acute respiratory syndrome coronavirus 2
  • vicugna pacos (alpaca)
KeywordsACE2 protein, human / Amino Acid Sequence / Angiotensin-Converting Enzyme 2 / Angiotensin-Converting Enzyme Inhibitors / Animals / Antibodies, Neutralizing / Antibodies, Viral / Betacoronavirus / Binding Sites / COVID-19 / Camelids, New World / Chlorocebus aethiops / Coronavirus Infections / Cryoelectron Microscopy / Epitopes / HEK293 Cells / Humans / Male / Models, Molecular / Pandemics / Peptidyl-Dipeptidase A / Pneumonia, Viral / Protein Binding / SARS-CoV-2 / Single-Domain Antibodies / Spike Glycoprotein, Coronavirus / Vero Cells / spike protein, SARS-CoV-2 / VIRAL PROTEIN / spike protein / neutralising antibody

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