Neutralizing nanobodies bind SARS-CoV-2 spike RBD and block interaction with ACE2

Neutralizing nanobodies bind SARS-CoV-2 spike RBD and block interaction with ACE2

The 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. Usi...

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Bibliographic Details
Main Authors: Huo, J, Le Bas, A, Ruza, RR, Duyvesten, HME, Mikolajek, H, Malinauskas, T, Tan, TK, Rijal, P, Dumoux, M, Ward, PN, Ren, J, Zhou, D, Harrison, PJ, Weckener, M, Clare, DK, Vogirala, VK, Radecke, J, Moynié, L, Zhao, Y, Gilbert-Jaramillo, J, Knight, ML, Tree, JA, Buttigieg, KR, Coombes, N, Elmore, MJ, Carroll, MW, Carrique, L, Shah, PNM, James, W, Townsend, AR, Stuart, DI, Owens, RJ, Naismith, JH
Format: Journal article
Language:English
Published: Springer Nature 2020
Description
Summary:The 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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