A Novel Method for Cysteine Arylation Directed by a Genetically Encodable Pi-clamp


This technology is a novel method for single-site-specific cysteine modification on peptide or protein molecules.

Problem Addressed

Thiol modification is an important tool in the chemical, biological, medical, and material sciences. As the only thiol-containing amino acid, cysteine is typically used for protein modification using thiol-based reactions. Despite the ubiquity of cysteine tagging, general chemical approaches do not exist for the site-specific modification of a single cysteine in the presence of other unprotected cysteines within the same peptide or protein chain. A highly efficient method that allows single-site-specific cysteine modification is needed to significantly expand the ability to modify biomolecules. The current technology features several advantages over existing peptide modification methods, including: specificity of thiols over other nucleophiles (e.g., amines, hydroxyls), excellent functional group tolerance, and mild reaction conditions. More importantly, cysteine modifications can be produced on a specific, peptide sequence. This invention has the potential to significantly expand the existing toolkit for modifying  biomolecules for research and therapeutics.


This technology is a novel chemistry approach for single-site-specific cysteine modification under physiologically relevant conditions. This technology is able to site specifically modify the cysteine in a four residue peptide sequence, X-Cys-Pro-X, where X is an aromatic amino acid (Phe, Trp, or Tyr), while other cysteines or reactive functional groups on the same peptide protein chain remain intact. In the specific sequence, the amino acid proline induces the formation of a β-turn that allows the two aromatic amino acid residues to form a local Pi-clamp around the cysteine thiol.


  • Specificity of thiols over other nucleophiles
  • Excellent functional group tolerance
  • Mild reaction conditions
  • Peptide sequence specificity