Bi-paratopic and multivalent VH domains block ACE2 binding and neutralize SARS-CoV-2

Autor: Jie Zhou, Nicholas J. Rettko, Katarina Pance, Beth S. Zha, Irene Lui, Jia Liu, Duy P. Nguyen, James Byrnes, Kevin Leung, James A. Wells, Paige Solomon, Kaitlin Schaefer, Shion A. Lim, Colton J Bracken, Xin X. Zhou
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Protein Conformation
Beta sheet
Plasma protein binding
Neutralization
Epitope
Protein structure
Models
Chlorocebus aethiops
Viral
Lung
Neutralizing
0303 health sciences
biology
Chemistry
030302 biochemistry & molecular biology
Spike Glycoprotein
Infectious Diseases
5.1 Pharmaceuticals
Pneumonia & Influenza
Angiotensin-Converting Enzyme 2
Development of treatments and therapeutic interventions
Antibody
Protein Binding
Biochemistry & Molecular Biology
Stereochemistry
QCRG Structural Biology Consortium
Antibodies
Vaccine Related
03 medical and health sciences
Medicinal and Biomolecular Chemistry
Clinical Research
Peptide Library
Biodefense
Animals
Humans
Protein Interaction Domains and Motifs
Binding site
Peptide library
Vero Cells
Molecular Biology
030304 developmental biology
Binding Sites
SARS-CoV-2
Prevention
Cryoelectron Microscopy
alpha-Helical
Molecular
Pneumonia
Cell Biology
Coronavirus
Emerging Infectious Diseases
Good Health and Well Being
HEK293 Cells
biology.protein
beta-Strand
Biochemistry and Cell Biology
Single-Chain Antibodies
Zdroj: Nature Chemical Biology
Nature chemical biology, vol 17, iss 1
ISSN: 1552-4469
1552-4450
DOI: 10.1038/s41589-020-00679-1
Popis: 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 (IC50) of 4.0 nM (180 ng ml-1). 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.
Databáze: OpenAIRE
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