8Q94

Crystal structure of The SARS-COV-2 BA.2.75 RBD with neutralizing-VHHs Re32D03 and Ma3B12

Summary for 8Q94

• Entry DOI: 10.2210/pdb8q94/pdb
• Descriptor: Spike protein S1, Nanobody Ma3B12, Nanobody Re32D03, ... (4 entities in total)
• Functional Keywords: neutralizing vhh, fold-promoter, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2; More
• Total number of polymer chains: 3
• Total formula weight: 49727.39

Authors

Aksu, M.,Guttler, T.,Gorlich, D. (deposition date: 2023-08-19, release date: 2023-12-20, Last modification date: 2023-12-27)

Primary citation

Aksu, M.,Kumar, P.,Guttler, T.,Taxer, W.,Gregor, K.,Mussil, B.,Rymarenko, O.,Stegmann, K.M.,Dickmanns, A.,Gerber, S.,Reineking, W.,Schulz, C.,Henneck, T.,Mohamed, A.,Pohlmann, G.,Ramazanoglu, M.,Mese, K.,Gross, U.,Ben-Yedidia, T.,Ovadia, O.,Fischer, D.W.,Kamensky, M.,Reichman, A.,Baumgartner, W.,von Kockritz-Blickwede, M.,Dobbelstein, M.,Gorlich, D.
Nanobodies to multiple spike variants and inhalation of nanobody-containing aerosols neutralize SARS-CoV-2 in cell culture and hamsters.
Antiviral Res., 221:105778-105778, 2023

PubMed Abstract: The ongoing threat of COVID-19 has highlighted the need for effective prophylaxis and convenient therapies, especially for outpatient settings. We have previously developed highly potent single-domain (VHH) antibodies, also known as nanobodies, that target the Receptor Binding Domain (RBD) of the SARS-CoV-2 Spike protein and neutralize the Wuhan strain of the virus. In this study, we present a new generation of anti-RBD nanobodies with superior properties. The primary representative of this group, Re32D03, neutralizes Alpha to Delta as well as Omicron BA.2.75; other members neutralize, in addition, Omicron BA.1, BA.2, BA.4/5, and XBB.1. Crystal structures of RBD-nanobody complexes reveal how ACE2-binding is blocked and also explain the nanobodies' tolerance to immune escape mutations. Through the cryo-EM structure of the Ma16B06-BA.1 Spike complex, we demonstrated how a single nanobody molecule can neutralize a trimeric spike. We also describe a method for large-scale production of these nanobodies in Pichia pastoris, and for formulating them into aerosols. Exposing hamsters to these aerosols, before or even 24 h after infection with SARS-CoV-2, significantly reduced virus load, weight loss and pathogenicity. These results show the potential of aerosolized nanobodies for prophylaxis and therapy of coronavirus infections.

PubMed: 38065245
DOI: 10.1016/j.antiviral.2023.105778

Experimental method

X-RAY DIFFRACTION (2.5 Å)