8SK5

Crystal structure of the SARS-CoV-2 neutralizing VHH 7A9 bound to the spike receptor binding domain

Summary for 8SK5

• Entry DOI: 10.2210/pdb8sk5/pdb
• Descriptor: Spike protein S1, anti-SARS-CoV-2 receptor binding domain VHH, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose, ... (4 entities in total)
• Functional Keywords: vhh, complex, antiviral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2; More
• Total number of polymer chains: 2
• Total formula weight: 44890.66

Authors

Noland, C.L.,Pande, K.,Zhang, L.,Zhou, H.,Galli, J.,Eddins, M.,Gomez-Llorente, Y. (deposition date: 2023-04-18, release date: 2023-08-16, Last modification date: 2024-10-16)

Primary citation

Hollingsworth, S.A.,Noland, C.L.,Vroom, K.,Saha, A.,Sam, M.,Gao, Q.,Zhou, H.,Grandy, D.U.,Singh, S.,Wen, Z.,Warren, C.,Ma, X.S.,Malashock, D.,Galli, J.,Go, G.,Eddins, M.,Mayhood, T.,Sathiyamoorthy, K.,Fridman, A.,Raoufi, F.,Gomez-Llorente, Y.,Patridge, A.,Tang, Y.,Chen, S.J.,Bailly, M.,Ji, C.,Kingsley, L.J.,Cheng, A.C.,Geierstanger, B.H.,Gorman, D.M.,Zhang, L.,Pande, K.
Discovery and multimerization of cross-reactive single-domain antibodies against SARS-like viruses to enhance potency and address emerging SARS-CoV-2 variants.
Sci Rep, 13:13668-13668, 2023

PubMed Abstract: Coronaviruses have been the causative agent of three epidemics and pandemics in the past two decades, including the ongoing COVID-19 pandemic. A broadly-neutralizing coronavirus therapeutic is desirable not only to prevent and treat COVID-19, but also to provide protection for high-risk populations against future emergent coronaviruses. As all coronaviruses use spike proteins on the viral surface to enter the host cells, and these spike proteins share sequence and structural homology, we set out to discover cross-reactive biologic agents targeting the spike protein to block viral entry. Through llama immunization campaigns, we have identified single domain antibodies (VHHs) that are cross-reactive against multiple emergent coronaviruses (SARS-CoV, SARS-CoV-2, and MERS). Importantly, a number of these antibodies show sub-nanomolar potency towards all SARS-like viruses including emergent CoV-2 variants. We identified nine distinct epitopes on the spike protein targeted by these VHHs. Further, by engineering VHHs targeting distinct, conserved epitopes into multi-valent formats, we significantly enhanced their neutralization potencies compared to the corresponding VHH cocktails. We believe this approach is ideally suited to address both emerging SARS-CoV-2 variants during the current pandemic as well as potential future pandemics caused by SARS-like coronaviruses.

PubMed: 37608223
DOI: 10.1038/s41598-023-40919-7

Experimental method

X-RAY DIFFRACTION (2.011 Å)