Discovery of Nanosota-2, -3, and -4 as super potent and broad-spectrum therapeutic nanobody candidates against COVID-19

Gang Ye, Ruangang Pan, Fan Bu, Jian Zheng, Alise Mendoza, Wei Wen, Lanying Du, Benjamin Spiller, Brian E. Wadzinski, Bin Liu, Stanley Perlman, Fang Li, Kanta Subbarao (Editor)

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Nanobodies are single-domain antibodies derived from camelid animals. Here, we discovered three anti-SARS-CoV-2 nanobodies, namely, Nanosota-2, -3, and -4, from an alpaca immunized with SARS-CoV spike protein. We further characterized the antiviral activities of these Fc-tag-fused nanobodies. Notably, Nanosota-2 inhibits the prototypic SARS-CoV-2 strain in vitro (with an IC50 of 2 pM) and in mice (at a dosage of 4 mg/kg or administered 18 hours post-challenge). These potency metrics are the best among known SARS-CoV-2 entry inhibitors. Moreover, Nanosota-3 effectively inhibits the omicron variant, both in vitro and in mice, regardless of the administration route (intraperitoneal or intranasal). Furthermore, Nanosota-3 has been biochemically engineered to inhibit both early and currently circulating subvariants of omicron. Additionally, Nanosota-4 uniquely inhibits both SARS-CoV-1 and SARS-CoV-2. Cryo-EM data revealed that the three nanobodies bind to functionally critical and non-overlapping regions in the spike protein. Given their cost-effectiveness, ease of adaptation to new viral strains, and potential use as inhalers, the Nanosota series are powerful therapeutic tools against coronavirus pandemics.

Original languageEnglish (US)
JournalJournal of virology
Volume97
Issue number11
DOIs
StatePublished - Nov 2023

Bibliographical note

Publisher Copyright:
Copyright © 2023 American Society for Microbiology. All Rights Reserved.

Keywords

  • ACE2
  • SARS-CoV-1
  • SARS-CoV-2
  • animal model
  • cryo-EM
  • omicron
  • receptor-binding domain
  • single-domain antibody from camelids
  • spike protein
  • virus neutralization
  • Antibodies, Neutralizing
  • Pandemics
  • Humans
  • Antibodies, Viral/therapeutic use
  • Single-Domain Antibodies/pharmacology
  • Spike Glycoprotein, Coronavirus
  • COVID-19/therapy

PubMed: MeSH publication types

  • Journal Article

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