A serum-stable RNA aptamer specific for SARS-CoV-2 neutralizes viral entry

Proc Natl Acad Sci U S A. 2021 Dec 14;118(50):e2112942118. doi: 10.1073/pnas.2112942118.


The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has created an urgent need for new technologies to treat COVID-19. Here we report a 2'-fluoro protected RNA aptamer that binds with high affinity to the receptor binding domain (RBD) of SARS-CoV-2 spike protein, thereby preventing its interaction with the host receptor ACE2. A trimerized version of the RNA aptamer matching the three RBDs in each spike complex enhances binding affinity down to the low picomolar range. Binding mode and specificity for the aptamer-spike interaction is supported by biolayer interferometry, single-molecule fluorescence microscopy, and flow-induced dispersion analysis in vitro. Cell culture experiments using virus-like particles and live SARS-CoV-2 show that the aptamer and, to a larger extent, the trimeric aptamer can efficiently block viral infection at low concentration. Finally, the aptamer maintains its high binding affinity to spike from other circulating SARS-CoV-2 strains, suggesting that it could find widespread use for the detection and treatment of SARS-CoV-2 and emerging variants.

Keywords: SARS-CoV-2 targeting; aptamer multimerization; aptamer selection; spike protein; viral neutralization.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin-Converting Enzyme 2 / metabolism
  • Aptamers, Nucleotide / chemistry
  • Aptamers, Nucleotide / metabolism
  • Aptamers, Nucleotide / pharmacology*
  • Humans
  • Mutation
  • Neutralization Tests
  • Nucleic Acid Conformation
  • Protein Binding / drug effects
  • Protein Interaction Domains and Motifs
  • SARS-CoV-2 / drug effects*
  • SARS-CoV-2 / physiology
  • SELEX Aptamer Technique
  • Spike Glycoprotein, Coronavirus / chemistry
  • Spike Glycoprotein, Coronavirus / genetics
  • Spike Glycoprotein, Coronavirus / metabolism
  • Virus Internalization / drug effects*


  • Aptamers, Nucleotide
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2