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Structure paper

TitleA potent pan-sarbecovirus neutralizing antibody resilient to epitope diversification.
Journal, issue, pagesCell, Vol. 187, Issue 25, Page 7196-7213.e26, Year 2024
Publish dateDec 12, 2024
AuthorsLaura E Rosen / M Alejandra Tortorici / Anna De Marco / Dora Pinto / William B Foreman / Ashley L Taylor / Young-Jun Park / Dana Bohan / Tyson Rietz / John M Errico / Kevin Hauser / Ha V Dang / Justin W Chartron / Martina Giurdanella / Giuseppe Cusumano / Christian Saliba / Fabrizia Zatta / Kaitlin R Sprouse / Amin Addetia / Samantha K Zepeda / Jack Brown / Jimin Lee / Exequiel Dellota / Anushka Rajesh / Julia Noack / Qiqing Tao / Yvonne DaCosta / Brian Tsu / Rima Acosta / Sambhavi Subramanian / Guilherme Dias de Melo / Lauriane Kergoat / Ivy Zhang / Zhuoming Liu / Barbara Guarino / Michael A Schmid / Gretja Schnell / Jessica L Miller / Florian A Lempp / Nadine Czudnochowski / Elisabetta Cameroni / Sean P J Whelan / Hervé Bourhy / Lisa A Purcell / Fabio Benigni / Julia di Iulio / Matteo Samuele Pizzuto / Antonio Lanzavecchia / Amalio Telenti / Gyorgy Snell / Davide Corti / David Veesler / Tyler N Starr /
PubMed AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evolution has resulted in viral escape from clinically authorized monoclonal antibodies (mAbs), creating a need for mAbs that are ...Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evolution has resulted in viral escape from clinically authorized monoclonal antibodies (mAbs), creating a need for mAbs that are resilient to epitope diversification. Broadly neutralizing coronavirus mAbs that are sufficiently potent for clinical development and retain activity despite viral evolution remain elusive. We identified a human mAb, designated VIR-7229, which targets the viral receptor-binding motif (RBM) with unprecedented cross-reactivity to all sarbecovirus clades, including non-ACE2-utilizing bat sarbecoviruses, while potently neutralizing SARS-CoV-2 variants since 2019, including the recent EG.5, BA.2.86, and JN.1. VIR-7229 tolerates extraordinary epitope variability, partly attributed to its high binding affinity, receptor molecular mimicry, and interactions with RBM backbone atoms. Consequently, VIR-7229 features a high barrier for selection of escape mutants, which are rare and associated with reduced viral fitness, underscoring its potential to be resilient to future viral evolution. VIR-7229 is a strong candidate to become a next-generation medicine.
External linksCell / PubMed:39383863 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution1.67 - 3.3 Å
Structure data

EMDB-43813, PDB-9asd:
VIR-7229 Fab fragment bound the SARS-CoV-2 BA.2.86 spike trimer (local refinement of the BA 2.86 RBD/VIR-7229 VHVL)
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-43842, PDB-9au2:
VIR-7229 Fab fragment bound the BA.2.86 spike trimer (global refinement)
Method: EM (single particle) / Resolution: 3.1 Å

PDB-8s6m:
SARS-CoV-2 BQ.1.1 RBD bound to the S2V29 and the S2H97 Fab fragments
Method: X-RAY DIFFRACTION / Resolution: 1.67 Å

PDB-9atm:
SARS-CoV-2 EG.5 RBD bound to the VIR-7229 and the S2H97 Fab fragments
Method: X-RAY DIFFRACTION / Resolution: 1.9 Å

PDB-9au1:
SARS-CoV-2 XBB.1.5 RBD bound to the VIR-7229 and the S309 Fab fragments
Method: X-RAY DIFFRACTION / Resolution: 2.41 Å

Chemicals

ChemComp-EDO:
1,2-ETHANEDIOL

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-NI:
NICKEL (II) ION

ChemComp-TRS:
2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL / pH buffer*YM

ChemComp-HOH:
WATER

ChemComp-CL:
Unknown entry

ChemComp-K:
Unknown entry

ChemComp-ACY:
ACETIC ACID

ChemComp-EPE:
4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID / pH buffer*YM

Source
  • Sarbecovirus
  • homo sapiens (human)
  • severe acute respiratory syndrome coronavirus 2
KeywordsVIRAL PROTEIN / Sarbecoviruses / Spike glycoprotein / fusion protein / neutralizing antibodies / inhibitor / Structural Genomics / Seattle Structural Genomics Center for Infectious Disease / SSGCID / VIRAL PROTEIN/IMMUNE SYSTEM / VIRAL PROTEIN-IMMUNE SYSTEM complex / Structural Genomics Consortium / SGC

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