Aptamer and N-Degron Ensemble (AptaGron) as a Target Protein Degradation Strategy

ACS Chem Biol. 2024 Dec 20;19(12):2462-2468. doi: 10.1021/acschembio.4c00536. Epub 2024 Dec 4.

Abstract

Target protein degradation (TPD) is a promising strategy for catalytic downregulation of target proteins through various cellular proteolytic pathways. Despite numerous reports on novel TPD mechanisms, the discovery of target-specific ligands remains a major challenge. Unlike small-molecule ligands, aptamers offer significant advantages, owing to their SELEX-based systematic screening method. To fully utilize aptamers for TPD, we designed an aptamer and N-degron ensemble system (AptaGron) that circumvents the need for synthetic conjugations between aptamers and proteolysis-recruiting units. In our AptaGron system, a peptide nucleic acid containing an N-degron peptide and a sequence complementary to the aptamer was designed. Using this system, we successfully degraded three target proteins, tau, nucleolin, and eukaryotic initiation factor 4E (eIF4E), which lack specific small-molecule ligands. Our results highlight the potential of the AptaGron approach as a robust platform for targeted protein degradation.

MeSH terms

  • Aptamers, Nucleotide* / chemistry
  • Aptamers, Nucleotide* / metabolism
  • Degrons
  • Eukaryotic Initiation Factor-4E* / metabolism
  • Humans
  • Nucleolin
  • Phosphoproteins* / metabolism
  • Proteolysis*
  • RNA-Binding Proteins* / metabolism
  • SELEX Aptamer Technique
  • tau Proteins / metabolism

Substances

  • RNA-Binding Proteins
  • Aptamers, Nucleotide
  • Phosphoproteins
  • Eukaryotic Initiation Factor-4E
  • tau Proteins
  • Nucleolin