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PreprintCited by 64SARS-CoV-2 and COVID-19 ResearchMonoclonal and Polyclonal Antibodies ResearchChemical Synthesis and Analysis

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Accelerating PERx Reaction Enables Covalent Nanobodies for Potent Neutralization of SARS-Cov-2 and Variants

Open access
Yu, Bingchen, Li, Shanshan, Tabata, Takako, Wang, Nanxi, Kumar, G. Renuka, Liu, Jun, Ott, Melanie M., Wang, Lei·2022·Chem
DOI 10.1101/2022.03.11.483867PMC PMC9288967

Preprint — published as 10.1016/j.chempr.2022.07.012

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Abstract

The long-lasting COVID-19 pandemic and increasing SARS-CoV-2 variants demand effective drugs for prophylactics and treatment. Protein-based biologics offer high specificity yet their noncovalent interactions often lead to drug dissociation and incomplete inhibition. Here we developed covalent nanobodies capable of binding with SARS-CoV-2 spike protein irreversibly via proximity-enabled reactive therapeutic (PERx) mechanism. A novel latent bioreactive amino acid FFY was designed and genetically encoded into nanobodies to accelerate PERx reaction rate. After covalent engineering, nanobodies binding with the Spike in the down state, but not in the up state, were discovered to possess striking enhancement in inhibiting viral infection. In comparison with the noncovalent wildtype nanobody, the FFY-incorporated covalent nanobody neutralized both authentic SARS-CoV-2 and its Alpha and Delta variants with potency drastically increased over tens of folds. This PERx-enabled covalent nanobody strategy and uncovered insights on potency increase can be valuable to developing effective therapeutics for various viral infections.

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Metadata

Authors
Yu, B., Li, S., Tabata, T., Wang, N., Kumar, G. R., Liu, J., Ott, M. M., & Wang, L.
Affiliations
  • University of California, San Francisco (US)
  • Gladstone Institutes (US)
Corresponding author
Wang, Lei
ORCID
Venue
Chem
Publisher
openRxiv
Published
2022-03-14
Volume
8
Issue
10
Pages
2766-2783
ISSN
2451-9294 (ISSN-L)
DOI
10.1101/2022.03.11.483867
PMC
PMC9288967
OpenAlex
W4285806329
Cited by
64
References
2
Citations by year
2026: 15 · 2025: 18 · 2024: 14 · 2023: 14 · 2022: 3
FWCI
5.99
Type
journal article
Language
en
Open access
Locations
  • Chem (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • Gladstone Institutes
  • National Institutes of Health
  • University of California, San Francisco (7030487)
  • National Cancer Institute (R01CA258300)
  • National Institute of General Medical Sciences (R01GM118384)
  • National Institute of Allergy and Infectious Diseases (R37AI083139)
Topics
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
  • Life Sciences › Immunology and Microbiology › Immunology › Monoclonal and Polyclonal Antibodies Research
  • Physical Sciences › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
Keywords
SARS-CoV-2, Omicron variant, neutralizing antibodies, COVID-19 treatment

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