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

DOI: 10.1038/s41594-020-0469-6 DOI Help

Authors: Jiangdong Huo (The Rosalind Franklin Institute; The Wellcome Centre for Human Genetics, University of Oxford; Protein Production UK) , Audrey Le Bas (The Wellcome Centre for Human Genetics, University of Oxford; Protein Production UK) , Reinis R. Ruza (The Wellcome Centre for Human Genetics, University of Oxford) , Helen M. E. Duyvesteyn (The Wellcome Centre for Human Genetics, University of Oxford) , Halina Mikolajek (Diamond Light Source) , Tomas Malinauskas (The Wellcome Centre for Human Genetics, University of Oxford) , Tiong Kit Tan (University of Oxford) , Pramila Rijal (University of Oxford) , Maud Dumoux (The Rosalind Franklin Institute) , Philip N. Ward (The Wellcome Centre for Human Genetics, University of Oxford; Protein Production UK) , Jingshan Ren (The Wellcome Centre for Human Genetics, University of Oxford) , Daming Zhou (The Wellcome Centre for Human Genetics, University of Oxford) , Peter J. Harrison (The Wellcome Centre for Human Genetics, University of Oxford; Protein Production UK) , Miriam Weckener (The Rosalind Franklin Institute) , Daniel K. Clare (Diamond Light Source) , Vinod K. Vogirala (Diamond Light Source) , Julika Radecke (Diamond Light Source) , Lucile Moynie (The Rosalind Franklin Institute) , Yuguang Zhao (The Wellcome Centre for Human Genetics, University of Oxford) , Javier Gilbert-jaramillo (University of Oxford) , Michael L. Knight (University of Oxford) , Julia A. Tree (Public Health England) , Karen R. Buttigieg (Public Health England) , Naomi Coombes (Public Health England) , Michael J. Elmore (Public Health England) , Miles W. Carroll (Public Health England) , Loic Carrique (Wellcome Centre for Human Genetics, University of Oxford) , Pranav N. M. Shah (The Wellcome Centre for Human Genetics, University of Oxford) , William James (University of Oxford) , Alain R. Townsend (University of Oxford) , David I. Stuart (The Wellcome Centre for Human Genetics, University of Oxford; Diamond Light Source) , Raymond J. Owens (The Rosalind Franklin Institute; The Wellcome Centre for Human Genetics, University of Oxford; Protein Production UK) , James H. Naismith (The Rosalind Franklin Institute; The Wellcome Centre for Human Genetics, University of Oxford; Protein Production UK)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Structural & Molecular Biology , VOL 21

State: Published (Approved)
Published: July 2020
Diamond Proposal Number(s): 27031 , 27051

Open Access Open Access

Abstract: 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.

Subject Areas: Biology and Bio-materials, Chemistry

Diamond Offline Facilities: Electron Bio-Imaging Centre (eBIC)
Instruments: I03-Macromolecular Crystallography , Krios I-Titan Krios I at Diamond

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s41594-020-0469-6.pdf