Improved Large-Scale Synthesis of Acridonylalanine for Diverse Peptide and Protein Applications

Bioconjug Chem. 2024 Dec 18;35(12):1913-1922. doi: 10.1021/acs.bioconjchem.4c00411. Epub 2024 Nov 12.

Abstract

Fluorescent unnatural amino acids give biochemists, biophysicists, and bioengineers new ways to probe the properties of proteins and peptides. Here, the synthesis of acridon-2-ylalanine (Acd) is optimized for large-scale production to enable ribosomal incorporation through genetic code expansion (GCE), and fluorenylmethoxycarbonyl (Fmoc)-protected Acd is prepared for solid-phase peptide synthesis (SPPS). We demonstrate the utility of Acd in several applications: first, Acd quenching by Tyr is used in the design of fluorescent protease sensors made by SPPS. Second, we demonstrate Acd incorporation into a lanthanide-binding peptide that is generated either by GCE or by SPPS and demonstrate the utility of Acd for sensitizing the emission of Eu3+. Finally, Acd is inserted into the intrinsically disordered protein, α-synuclein, using GCE and used to study ion binding and aggregation.

MeSH terms

  • Alanine* / analogs & derivatives
  • Alanine* / chemical synthesis
  • Alanine* / chemistry
  • Fluorescent Dyes / chemical synthesis
  • Fluorescent Dyes / chemistry
  • Peptides* / chemical synthesis
  • Peptides* / chemistry
  • Proteins / chemical synthesis
  • Proteins / chemistry
  • Solid-Phase Synthesis Techniques* / methods
  • alpha-Synuclein / chemistry

Substances

  • Alanine
  • Peptides
  • Proteins
  • alpha-Synuclein
  • Fluorescent Dyes