Journal
NATURE CHEMICAL BIOLOGY
Volume 17, Issue 1, Pages 113-121Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41589-020-00679-1
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Funding
- NCI [R35 GM122451-01]
- UCSF Program for Breakthrough Biomedical Research (PBBR)
- Fast Grants from Emergent Ventures at the Mercatus Center, George Mason University [2154]
- Harrington Discovery Institute [GA33116]
- National Institutes of Health National Cancer Institute [F32 5F32CA239417, 5F32CA236151-02, HL007185]
- National Science Foundation (GRFP)
- UCSF-PBBR Postdoctoral Independent Research Award - Sandler Foundation
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This study presents a strategy to rapidly identify and assemble synthetic human VH domains for neutralizing SARS-CoV-2, which was proven to be effective through experimental validation.
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.
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