The development of Nanosota- 1 as anti-SARS-CoV-2 nanobody drug candidates

Elife. 2021 Aug 2;10:e64815. doi: 10.7554/eLife.64815.

Abstract

Combating the COVID-19 pandemic requires potent and low-cost therapeutics. We identified a series of single-domain antibodies (i.e., nanobody), Nanosota-1, from a camelid nanobody phage display library. Structural data showed that Nanosota-1 bound to the oft-hidden receptor-binding domain (RBD) of SARS-CoV-2 spike protein, blocking viral receptor angiotensin-converting enzyme 2 (ACE2). The lead drug candidate possessing an Fc tag (Nanosota-1C-Fc) bound to SARS-CoV-2 RBD ~3000 times more tightly than ACE2 did and inhibited SARS-CoV-2 pseudovirus ~160 times more efficiently than ACE2 did. Administered at a single dose, Nanosota-1C-Fc demonstrated preventive and therapeutic efficacy against live SARS-CoV-2 infection in both hamster and mouse models. Unlike conventional antibodies, Nanosota-1C-Fc was produced at high yields in bacteria and had exceptional thermostability. Pharmacokinetic analysis of Nanosota-1C-Fc documented an excellent in vivo stability and a high tissue bioavailability. As effective and inexpensive drug candidates, Nanosota-1 may contribute to the battle against COVID-19.

Keywords: ACE2; COVID-19; animal model; crystal structures; drug pharmacokinetics; infectious disease; microbiology; single-chain antibody from camelids; spike protein receptor-binding domain; virus; virus neutralization.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin-Converting Enzyme 2 / metabolism
  • Animals
  • Antibodies, Neutralizing / immunology
  • Antibodies, Viral / immunology*
  • COVID-19 / immunology
  • COVID-19 / metabolism
  • COVID-19 Drug Treatment*
  • HEK293 Cells
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Models, Molecular
  • Pandemics
  • Protein Binding
  • Protein Conformation
  • Receptors, Virus / immunology
  • Receptors, Virus / metabolism
  • SARS-CoV-2 / drug effects*
  • Single-Domain Antibodies / chemistry
  • Single-Domain Antibodies / pharmacology*
  • Spike Glycoprotein, Coronavirus / metabolism

Substances

  • Antibodies, Neutralizing
  • Antibodies, Viral
  • Receptors, Virus
  • Single-Domain Antibodies
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2
  • Angiotensin-Converting Enzyme 2