Aptamer Blocking Strategy Inhibits SARS-CoV-2 Virus Infection

Angew Chem Int Ed Engl. 2021 Apr 26;60(18):10266-10272. doi: 10.1002/anie.202100225. Epub 2021 Mar 10.


The COVID-19 pandemic caused by SARS-CoV-2 is threating global health. Inhibiting interaction of the receptor-binding domain of SARS-CoV-2 S protein (SRBD ) and human ACE2 receptor is a promising treatment strategy. However, SARS-CoV-2 neutralizing antibodies are compromised by their risk of antibody-dependent enhancement (ADE) and unfavorably large size for intranasal delivery. To avoid these limitations, we demonstrated an aptamer blocking strategy by engineering aptamers' binding to the region on SRBD that directly mediates ACE2 receptor engagement, leading to block SARS-CoV-2 infection. With aptamer selection against SRBD and molecular docking, aptamer CoV2-6 was identified and applied to prevent, compete with, and substitute ACE2 from binding to SRBD . CoV2-6 was further shortened and engineered as a circular bivalent aptamer CoV2-6C3 (cb-CoV2-6C3) to improve the stability, affinity, and inhibition efficacy. cb-CoV2-6C3 is stable in serum for more than 12 h and can be stored at room temperature for more than 14 days. Furthermore, cb-CoV2-6C3 binds to SRBD with high affinity (Kd =0.13 nM) and blocks authentic SARS-CoV-2 virus with an IC50 of 0.42 nM.

Keywords: SARS-CoV-2; aptamers; neutralization therapy; viral infections.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin-Converting Enzyme 2 / metabolism*
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Aptamers, Nucleotide / chemistry
  • Aptamers, Nucleotide / pharmacology*
  • COVID-19 / metabolism
  • COVID-19 Drug Treatment*
  • Drug Discovery
  • HEK293 Cells
  • Humans
  • Molecular Docking Simulation
  • Protein Binding / drug effects
  • Protein Interaction Domains and Motifs / drug effects
  • SARS-CoV-2 / chemistry
  • SARS-CoV-2 / drug effects*
  • SARS-CoV-2 / physiology
  • Spike Glycoprotein, Coronavirus / chemistry
  • Spike Glycoprotein, Coronavirus / metabolism*


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