Evolving A RIG-I Antagonist: A Modified DNA Aptamer Mimics Viral RNA

J Mol Biol. 2021 Oct 15;433(21):167227. doi: 10.1016/j.jmb.2021.167227. Epub 2021 Sep 3.


Vertebrate organisms express a diversity of protein receptors that recognize and respond to the presence of pathogenic molecules, functioning as an early warning system for infection. As a result of mutation or dysregulated metabolism, these same innate immune receptors can be inappropriately activated, leading to inflammation and disease. One of the most important receptors for detection and response to RNA viruses is called RIG-I, and dysregulation of this protein is linked with a variety of disease states. Despite its central role in inflammatory responses, antagonists for RIG-I are underdeveloped. In this study, we use invitro selection from a pool of modified DNA aptamers to create a high affinity RIG-I antagonist. A high resolution crystal structure of the complex reveals molecular mimicry between the aptamer and the 5'-triphosphate terminus of viral ligands, which bind to the same amino acids within the CTD recognition platform of the RIG-I receptor. Our study suggests a powerful, generalizable strategy for generating immunomodulatory drugs and mechanistic tool compounds.

Keywords: DNA structure; in-vitro; innate immunity; molecular recognition; nucleic acid folding.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Viral / chemistry*
  • Antigens, Viral / metabolism
  • Aptamers, Nucleotide / chemistry*
  • Aptamers, Nucleotide / metabolism
  • Binding Sites
  • Cloning, Molecular
  • Crystallography, X-Ray
  • DEAD Box Protein 58 / chemistry*
  • DEAD Box Protein 58 / genetics
  • DEAD Box Protein 58 / metabolism
  • Escherichia coli / genetics
  • Escherichia coli / metabolism
  • Gene Expression
  • Genetic Vectors / chemistry
  • Genetic Vectors / metabolism
  • Humans
  • Immunologic Factors / chemistry*
  • Immunologic Factors / metabolism
  • Kinetics
  • Models, Molecular
  • Molecular Mimicry
  • Mutation
  • Nucleic Acid Conformation
  • Protein Binding
  • Protein Conformation, alpha-Helical
  • Protein Conformation, beta-Strand
  • Protein Interaction Domains and Motifs
  • RNA, Viral / chemistry*
  • RNA, Viral / metabolism
  • Receptors, Immunologic / chemistry*
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / metabolism
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • SELEX Aptamer Technique


  • Antigens, Viral
  • Aptamers, Nucleotide
  • Immunologic Factors
  • RNA, Viral
  • Receptors, Immunologic
  • Recombinant Proteins
  • DDX58 protein, human
  • DEAD Box Protein 58