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Tyrosinase-Catalyzed Peptide Macrocyclization for mRNA Display.

Matthew C Fleming^1,2, Matthew M Bowler^1,2, Rodney Park³

¹Division 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.

Journal of the American Chemical Society

|May 8, 2023

Summary

We developed a new method using tyrosinase to create macrocyclic peptides for mRNA display. This technique successfully discovered potent ligands targeting melanoma-associated antigen A4 (MAGE-A4).

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Area of Science:

Biochemistry
Molecular Biology
Medicinal Chemistry

Background:

Messenger RNA (mRNA) display is a powerful method for discovering high-affinity peptide ligands.
Limited cyclization chemistries are compatible with mRNA display, restricting macrocyclic peptide discovery.
Tyrosinase enzyme catalyzes the oxidation of tyrosine to a reactive o-quinone.

Purpose of the Study:

To introduce and characterize a novel tyrosinase-mediated peptide cyclization compatible with mRNA display.
To apply this method to discover macrocyclic ligands targeting the melanoma-associated antigen A4 (MAGE-A4).

Main Methods:

Peptides containing tyrosine and cysteine residues were treated with tyrosinase for cyclization.
The tyrosinase-mediated cyclization was characterized for its applicability to various macrocycle sizes and scaffolds.
The developed method was combined with mRNA display to screen for MAGE-A4 targeting ligands.

Main Results:

Tyrosinase treatment rapidly cyclized peptides containing tyrosine and cysteine.
The cyclization method proved versatile across different macrocycle sizes and scaffolds.
Discovered macrocyclic ligands potently inhibited the MAGE-A4 binding axis with nanomolar IC50 values.
Macrocyclic ligands demonstrated a significant advantage over non-cyclized analogues, with IC50 values decreasing approximately 40-fold.

Conclusions:

Tyrosinase-mediated cyclization is a broadly applicable and efficient method for generating macrocyclic peptides.
Combining tyrosinase cyclization with mRNA display is effective for discovering potent macrocyclic ligands.
The discovered macrocyclic ligands targeting MAGE-A4 show therapeutic potential for melanoma treatment.