Journal Article

PUBDB-2025-03591

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png A critical residue in a conserved RBD epitopethe determines neutralization breadth of pan-sarbecovirus antibodies with recurring YYDRxxG motifs

Stein, S. C. ; Ssebyatika, G. ; Benecke, T. ; Ströh, L. ; Rajak, M. K. ; Vollmer, B.CSSB* ; Menz, S. ; Waldmann, J.-Y. ; Tipp, S. N. ; Ochulor, O. ; Herold, E. ; Schwarzloh, B. ; Mutschall, D. ; Zischke, J. ; Schneider, T. ; Hinrichs, I. ; Blasczyk, R. ; Kleine-Weber, H. ; Hoffmann, M. ; Klein, F. ; Kaiser, F. K. ; Gonzalez-Hernandez, M. ; Armando, F. ; Ciurkiewicz, M. ; Beythien, G. ; Pöhlmann, S. ; Baumgärtner, W. ; Gruenewald, K.CSSB*DESY* ; Osterhaus, A. ; Schulz, T. F. (Corresponding author) ; Krey, T. (Corresponding author) ; Hansen, G. (Corresponding author)

2025
American Society for Microbiology Washington, DC

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Please use a persistent id in citations: doi:10.1128/mbio.00606-25  doi:10.3204/PUBDB-2025-03591

Abstract: The emergence of pandemic coronaviruses remains a global health concern, highlighting the need for broadly neutralizing antibodies (bnAbs) that can target multiple sarbecoviruses. In this study, we isolated and characterized a novel antibody, pT1679, that demonstrates exceptional neutralization breadth. The antibody prevented infection with SARS-CoV-2 variants of concern, such as Omicron BA.1, and effectively neutralized pseudotyped viruses displaying S proteins from many SARS-CoV-2 variants and various bat and pangolin sarbecoviruses, including both SARS-CoV-like and SARS-CoV-2-like viruses. In addition, pT1679 reduced the viral load in the lung of infected Syrian hamsters and prevented the severe lung pathology typical for SARS-CoV-2 infections. The cryo-electron microscopy structure of pT1679 in complex with SARS-CoV-2 S revealed that the antibody employs a YYDRxxG motif to recognize a highly conserved epitope on the RBD. Through detailed structural analysis, mutagenesis studies, and binding assays, we identified RBD residue 384 as a critical determinant of antibody recognition. Structure-function analyses of several related bnAbs, such as COVA1-16, allowed for the classification of YYDRxxG antibodies into two distinct groups that differ in neutralization breadth. Our findings provide crucial insights into the molecular basis of broad Sarbecovirus neutralization and offer strategic guidance for selecting therapeutic antibodies in preparation for future Sarbecovirus outbreaks.

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Contributing Institute(s):

1. CSSB - Leibniz-Institut für Experimentelle Virologie (LIV) - Kay Grünewald (CSSB-LIV-KG)

Research Program(s):

1. 633 - Life Sciences – Building Blocks of Life: Structure and Function (POF4-633) (POF4-633)
2. DFG project G:(GEPRIS)390874280 - EXC 2155: RESIST - Resolving Infection Susceptibility (390874280) (390874280)
3. GRK 2485 - GRK 2485: Virusdetektion, Pathogenese und Intervention (VIPER) (398066876) (398066876)
4. DFG project G:(GEPRIS)158989968 - SFB 900: Chronische Infektionen: Mikrobielle Persistenz und ihre Kontrolle (158989968) (158989968)
5. DFG project G:(GEPRIS)439226007 - Hochdurchsatz Imaging System zur Analyse von Proteinkristallen (439226007) (439226007)

Experiment(s):

1. No specific instrument

Appears in the scientific report 2025

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