About: Bi-paratopic and multivalent human VH domains neutralize SARS-CoV-2 by targeting distinct epitopes within the ACE2 binding interface of Spike

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About: Bi-paratopic and multivalent human VH domains neutralize SARS-CoV-2 by targeting distinct epitopes within the ACE2 binding interface of Spike Goto Sponge NotDistinct Permalink

An Entity of Type : schema:ScholarlyArticle, within Data Space : covidontheweb.inria.fr associated with source document(s)

Attributes	Values
type	Academic Article research paper schema:ScholarlyArticle
isDefinedBy	Covid-on-the-Web dataset
has title	Bi-paratopic and multivalent human VH domains neutralize SARS-CoV-2 by targeting distinct epitopes within the ACE2 binding interface of Spike
Creator	Liu, Jia Zhou, Jie Zhou, Xin Byrnes, James Leung, Kevin Lim, Shion Lui, Irene Nguyen, Duy Pance, Katarina Rettko, Nicholas Schaefer, Kaitlin Solomon, Paige Wells, James Zha, Beth Bracken, Colton
Source	BioRxiv; Medline; PMC
abstract	Neutralizing agents against SARS-CoV-2 are urgently needed for treatment and prophylaxis of COVID-19. Here, we present a strategy to rapidly identify and assemble synthetic human variable heavy (VH) domain binders with high affinity toward neutralizing epitopes without the need for high-resolution structural information. We constructed a VH-phage library and targeted a known neutralizing site, the angiotensin-converting enzyme 2 (ACE2) binding interface of the trimeric SARS-CoV-2 Spike receptor-binding domain (Spike-RBD). Using a masked selection approach, we identified 85 unique VH binders to two non-overlapping epitopes within the ACE2 binding site on Spike-RBD. This enabled us to systematically link these VH domains into multivalent and bi-paratopic formats. These multivalent and bi-paratopic VH constructs showed a marked increase in affinity to Spike (up to 600-fold) and neutralization potency (up to 1400-fold) on pseudotyped SARS-CoV-2 virus when compared to the standalone VH domains. The most potent binder, a trivalent VH, neutralized authentic SARS-CoV-2 with half-minimal inhibitory concentration (IC(50)) of 4.0 nM (180 ng/mL). A cryo-EM structure of the trivalent VH bound to Spike shows each VH domain bound an RBD at the ACE2 binding site, explaining its increased neutralization potency and confirming our original design strategy. Our results demonstrate that targeted selection and engineering campaigns using a VH-phage library can enable rapid assembly of highly avid and potent molecules towards therapeutically important protein interfaces.
has issue date	2020-08-10(xsd:dateTime)
bibo:doi	10.1101/2020.08.08.242511
bibo:pmid	32817948
has license	cc-by-nc-nd
sha1sum (hex)	36176e9e0b5861e1b725ae1fe278c09b8fe0ae0e
schema:url	https://doi.org/10.1101/2020.08.08.242511
resource representing a document's title	Bi-paratopic and multivalent human VH domains neutralize SARS-CoV-2 by targeting distinct epitopes within the ACE2 binding interface of Spike
has PubMed Central identifier	PMC7430580
has PubMed identifier	32817948
schema:publication	bioRxiv
resource representing a document's body	covid:36176e9e0b5861e1b725ae1fe278c09b8fe0ae0e#body_text
is schema:about of	named entity 'PRESENT' named entity 'DESIGN' named entity 'SARS-COV-2' named entity 'RAPID' named entity 'ITS' named entity 'ENGINEERING' named entity 'UNIQUE' named entity 'ENABLE' named entity 'potency' named entity 'binding site' named entity 'protein' named entity 'SARS-CoV-2' named entity 'COVID-19' named entity 'ACE2' named entity 'ng/mL' named entity 'phage' named entity 'multivalent' named entity 'NGS' named entity 'nanobodies' named entity 'avidity' named entity 'RBDs' named entity 'ACE2' named entity 'cloned' named entity 'ACE2' named entity 'single-domain' named entity 'binding mechanism' named entity 'ACE2' named entity 'E. coli' named entity 'GE Healthcare' named entity 'phage' named entity 'nanobodies' named entity 'VH2' named entity 'antigen' named entity 'multivalent' named entity 'VH2' named entity 'ACE2' named entity 'PDB' named entity 'Nanobodies' named entity 'E. coli' named entity 'E. coli' named entity 'NGS' named entity 'binding affinity' named entity 'SARS-CoV-2' named entity 'virus' named entity 'IC50' named entity 'llama' named entity 'autoinduction' named entity 'RBD' named entity 'antibody' named entity '4 nm' named entity 'antigen' named entity 'binding site' named entity 'Pseudotyped' named entity 'rigid body' named entity 'epithelial cells' named entity 'VH2' named entity 'VH2' named entity 'serology' named entity 'endotoxin' named entity 'IC50' named entity 'VH2' named entity 'trivalent' named entity 'mutagenesis' named entity 'VH2' named entity 'ectodomain' named entity 'nanobody' named entity 'UCSF'

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