2. Academic Validation
  3. Tyrosinase-Catalyzed Peptide Macrocyclization for mRNA Display

Tyrosinase-Catalyzed Peptide Macrocyclization for mRNA Display

  • J Am Chem Soc. 2023 May 17;145(19):10445-10450. doi: 10.1021/jacs.2c12629.
Matthew C Fleming 1 2,  Matthew M Bowler 1 2,  Rodney Park 3,  Konstantin I Popov 1 2 3,  Albert A Bowers 1 2 4
Affiliations

Affiliations

  • 1 Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, 301 Pharmacy Lane, Chapel Hill, North Carolina 27599, United States.
  • 2 Center for Integrative Chemical Biology and Drug Discovery, Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, United States.
  • 3 Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina 27599, United States.
  • 4 Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
PMID: 37155687 DOI: 10.1021/jacs.2c12629
Abstract

mRNA display of macrocyclic Peptides has proven itself to be a powerful technique to discover high-affinity ligands for a protein target. However, only a limited number of cyclization chemistries are known to be compatible with mRNA display. Tyrosinase is a copper-dependent oxidase that oxidizes tyrosine phenol to an electrophilic o-quinone, which is readily attacked by cysteine thiol. Here we show that Peptides containing tyrosine and cysteine are rapidly cyclized upon Tyrosinase treatment. Characterization of the cyclization reveals it to be widely applicable to multiple macrocycle sizes and scaffolds. We combine tyrosinase-mediated cyclization with mRNA display to discover new macrocyclic ligands targeting melanoma-associated antigen A4 (MAGE-A4). These macrocycles potently inhibit the MAGE-A4 binding axis with nanomolar IC50 values. Importantly, macrocyclic ligands show clear advantage over noncyclized analogues with ∼40-fold or greater decrease in IC50 values.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-P10676
    Macrocyclic Peptide