A Modular PMDA Linker Enables Lysine-Selective Cyclization of Unprotected Peptides and Automated Macrocycle Assembly

Area of Science:

• Chemical Biology
• Medicinal Chemistry
• Synthetic Chemistry

Background:

• Macrocyclic peptide stapling enhances stability and function.
• Current methods lack chemoselectivity, modularity, or automation compatibility.

Purpose of the Study:

• Develop a novel, chemoselective, and automation-ready peptide stapling platform.
• Utilize pyromellitic dianhydride (PMDA) for lysine-lysine stapling.

Main Methods:

• Employed a pyromellitic dianhydride (PMDA)-based Lys-Lys stapling strategy.
• Achieved intramolecular bis-amidation of unprotected peptides under mild conditions.
• Demonstrated selectivity for lysine ε-amines, tolerating other nucleophiles like cysteine.

Main Results:

• PMDA acts as a tetrafunctional scaffold for macrocyclization and installing carboxylate handles.
• The method is highly chemoselective for lysine residues.
• Resulting macrocycles allow for stepwise bicyclization and postcyclization conjugation.
• Applied to antimicrobial peptides, it enhanced conformational constraint and proteolytic stability.
• Demonstrated compatibility with automated solid-phase peptide synthesis.

Conclusions:

• The PMDA-based Lys-Lys stapling platform offers a versatile and automation-ready solution for macrocyclic peptide synthesis.
• This approach facilitates rapid assembly and functional diversification of peptides.
• The strategy improves peptide stability and opens avenues for drug development and bioconjugation.