Bi-paratopic and multivalent VH domains block ACE2 binding and neutralize SARS-CoV-2.
Nat Chem Biol
; 17(1): 113-121, 2021 01.
Article
in English
| MEDLINE | ID: covidwho-882912
ABSTRACT
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.
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Antibodies, Neutralizing
/
Single-Chain Antibodies
/
Spike Glycoprotein, Coronavirus
/
Angiotensin-Converting Enzyme 2
/
Antibodies, Viral
Type of study:
Randomized controlled trials
Limits:
Animals
/
Humans
Language:
English
Journal:
Nat Chem Biol
Journal subject:
Biology
/
Chemistry
Year:
2021
Document Type:
Article
Affiliation country:
S41589-020-00679-1
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