Biparatopic sybodies neutralize SARS-CoV-2 variants of concern and mitigate drug resistance.
EMBO Rep
; 23(4): e54199, 2022 04 05.
Article
in English
| MEDLINE | ID: covidwho-1732510
ABSTRACT
The ongoing COVID-19 pandemic represents an unprecedented global health crisis. Here, we report the identification of a synthetic nanobody (sybody) pair, Sb#15 and Sb#68, that can bind simultaneously to the SARS-CoV-2 spike RBD and efficiently neutralize pseudotyped and live viruses by interfering with ACE2 interaction. Cryo-EM confirms that Sb#15 and Sb#68 engage two spatially discrete epitopes, influencing rational design of bispecific and tri-bispecific fusion constructs that exhibit up to 100- and 1,000-fold increase in neutralization potency, respectively. Cryo-EM of the sybody-spike complex additionally reveals a novel up-out RBD conformation. While resistant viruses emerge rapidly in the presence of single binders, no escape variants are observed in the presence of the bispecific sybody. The multivalent bispecific constructs further increase the neutralization potency against globally circulating SARS-CoV-2 variants of concern. Our study illustrates the power of multivalency and biparatopic nanobody fusions for the potential development of therapeutic strategies that mitigate the emergence of new SARS-CoV-2 escape mutants.
Keywords
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Single-Domain Antibodies
/
COVID-19 Drug Treatment
Topics:
Variants
Limits:
Humans
Language:
English
Journal:
EMBO Rep
Journal subject:
Molecular Biology
Year:
2022
Document Type:
Article
Affiliation country:
Embr.202154199
Similar
MEDLINE
...
LILACS
LIS