Biparatopic sybodies neutralize SARS-CoV-2 variants of concern and mitigate drug resistance.

Walter, Justin D; Scherer, Melanie; Hutter, Cedric A J; Garaeva, Alisa A; Zimmermann, Iwan; Wyss, Marianne; Rheinberger, Jan; Ruedin, Yelena; Earp, Jennifer C; Egloff, Pascal; Sorgenfrei, Michèle; Hürlimann, Lea M; Gonda, Imre; Meier, Gianmarco; Remm, Sille; Thavarasah, Sujani; van Geest, Geert; Bruggmann, Rémy; Zimmer, Gert; Slotboom, Dirk J; ... (2022). Biparatopic sybodies neutralize SARS-CoV-2 variants of concern and mitigate drug resistance. EMBO reports, 23(4), e54199. EMBO press 10.15252/embr.202154199

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH) > Experimental Clinical Research
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Institute of Virology and Immunology
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Institute of Veterinary Bacteriology

UniBE Contributor:

Scherer, Melanie; Wyss, Marianne; Ruedin, Yelena; Bruggmann, Rémy; Zimmer, Gert and Plattet, Philippe

Subjects:

600 Technology > 630 Agriculture

ISSN:

1469-3178

Publisher:

EMBO press

Language:

English

Submitter:

Pubmed Import

Date Deposited:

08 Mar 2022 12:08

Last Modified:

08 Apr 2022 00:14

Publisher DOI:

10.15252/embr.202154199

PubMed ID:

35253970

Uncontrolled Keywords:

SARS-CoV-2 escape mutants sybodies synthetic nanobodies variants of concern

BORIS DOI:

10.48350/166739

URI:

https://boris.unibe.ch/id/eprint/166739

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