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Nat. Struct. Mol. Biol. · Sep 2020
Neutralizing nanobodies bind SARS-CoV-2 spike RBD and block interaction with ACE2.
- Jiandong Huo, Audrey Le Bas, Reinis R Ruza, Helen M E Duyvesteyn, Halina Mikolajek, Tomas Malinauskas, Tiong Kit Tan, Pramila Rijal, Maud Dumoux, Philip N Ward, Jingshan Ren, Daming Zhou, Peter J Harrison, Miriam Weckener, Daniel K Clare, Vinod K Vogirala, Julika Radecke, Lucile Moynié, Yuguang Zhao, Javier Gilbert-Jaramillo, Michael L Knight, Julia A Tree, Karen R Buttigieg, Naomi Coombes, Michael J Elmore, Miles W Carroll, Loic Carrique, Pranav N M Shah, William James, Alain R Townsend, David I Stuart, Raymond J Owens, and James H Naismith.
- Structural Biology, The Rosalind Franklin Institute, Harwell Science & Innovation Campus, Didcot, UK.
- Nat. Struct. Mol. Biol. 2020 Sep 1; 27 (9): 846-854.
AbstractThe SARS-CoV-2 virus is more transmissible than previous coronaviruses and causes a more serious illness than influenza. The SARS-CoV-2 receptor binding domain (RBD) of the spike protein binds to the human angiotensin-converting enzyme 2 (ACE2) receptor as a prelude to viral entry into the cell. Using a naive llama single-domain antibody library and PCR-based maturation, we have produced two closely related nanobodies, H11-D4 and H11-H4, that bind RBD (KD of 39 and 12 nM, respectively) and block its interaction with ACE2. Single-particle cryo-EM revealed that both nanobodies bind to all three RBDs in the spike trimer. Crystal structures of each nanobody-RBD complex revealed how both nanobodies recognize the same epitope, which partly overlaps with the ACE2 binding surface, explaining the blocking of the RBD-ACE2 interaction. Nanobody-Fc fusions showed neutralizing activity against SARS-CoV-2 (4-6 nM for H11-H4, 18 nM for H11-D4) and additive neutralization with the SARS-CoV-1/2 antibody CR3022.
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