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TitleBi-paratopic and multivalent VH domains block ACE2 binding and neutralize SARS-CoV-2.
Journal, issue, pagesNat Chem Biol, Vol. 17, Issue 1, Page 113-121, Year 2021
Publish dateOct 20, 2020
AuthorsColton J Bracken / Shion A Lim / Paige Solomon / Nicholas J Rettko / Duy P Nguyen / Beth Shoshana Zha / Kaitlin Schaefer / James R Byrnes / Jie Zhou / Irene Lui / Jia Liu / Katarina Pance / / Xin X Zhou / Kevin K Leung / James A Wells /
PubMed AbstractNeutralizing agents against SARS-CoV-2 are urgently needed for the treatment and prophylaxis of COVID-19. Here, we present a strategy to rapidly identify and assemble synthetic human variable heavy ...Neutralizing agents against SARS-CoV-2 are urgently needed for the treatment and prophylaxis of COVID-19. Here, we present a strategy to rapidly identify and assemble synthetic human variable heavy (VH) domains toward neutralizing epitopes. We constructed a VH-phage library and targeted the angiotensin-converting enzyme 2 (ACE2) binding interface of the SARS-CoV-2 Spike receptor-binding domain (Spike-RBD). Using a masked selection approach, we identified VH binders to two non-overlapping epitopes and further assembled these into multivalent and bi-paratopic formats. These VH constructs showed increased affinity to Spike (up to 600-fold) and neutralization potency (up to 1,400-fold) on pseudotyped SARS-CoV-2 virus when compared to standalone VH domains. The most potent binder, a trivalent VH, neutralized authentic SARS-CoV-2 with a half-maximal inhibitory concentration (IC) of 4.0 nM (180 ng ml). A cryo-EM structure of the trivalent VH bound to Spike shows each VH domain engaging an RBD at the ACE2 binding site, confirming our original design strategy.
External linksNat Chem Biol / PubMed:33082574
MethodsEM (single particle)
Resolution3.2 - 6 Å
Structure data

EMDB-22514, PDB-7jwb:
SARS CoV2 Spike ectodomain with engineered trimerized VH binder
Method: EM (single particle) / Resolution: 3.2 Å

Source
  • homo sapiens (human)
  • severe acute respiratory syndrome coronavirus 2
KeywordsACE2 protein, human / Angiotensin-Converting Enzyme 2 / Animals / Antibodies, Neutralizing / Antibodies, Viral / Binding Sites, Antibody / Chlorocebus aethiops / Cryoelectron Microscopy / HEK293 Cells / Humans / Models, Molecular / Peptide Library / Protein Binding / Protein Conformation, alpha-Helical / Protein Conformation, beta-Strand / Protein Interaction Domains and Motifs / SARS-CoV-2 / Single-Chain Antibodies / Spike Glycoprotein, Coronavirus / Vero Cells / spike protein, SARS-CoV-2 / VIRAL PROTEIN/IMMUNE SYSTEM / Spike / VH / SARS / CoV2 / VIRAL PROTEIN-IMMUNE SYSTEM complex

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