Development of an oxazole-based cleavable linker for peptides

Area of Science:

• Organic Chemistry
• Bioconjugation Chemistry
• Peptide Chemistry

Background:

• Peptide-based linkers are crucial for various applications, including drug delivery and diagnostics.
• Existing linkers often lack stability or require harsh conditions for cleavage.
• A need exists for robust and selectively cleavable linkers in peptide chemistry.

Purpose of the Study:

• To develop a new oxazole-based cleavable linker for controlled peptide release.
• To demonstrate the stability and cleavage properties of the oxazole linker.
• To explore its utility in releasing peptides from small molecules and in orthogonal release strategies.

Main Methods:

• Synthesis of oxazole-based linkers using standard solid-phase peptide coupling.
• Conjugation of oxazole linkers to diverse peptides, including those with unnatural amino acids.
• Cleavage studies using single-electron oxidants, such as cerium ammonium nitrate (CAN).

Main Results:

• Successful synthesis and attachment of oxazole linkers to peptides.
• Rapid and efficient cleavage of peptide-oxazole conjugates mediated by single-electron oxidation.
• Demonstration of linker utility in releasing peptides from small molecules.
• Successful orthogonal release of cargo from peptides with multiple cleavable linkers.

Conclusions:

• Oxazole linkers offer a novel, stable, and selectively cleavable method for peptide release.
• This technology represents the first peptide-based linker cleaved by single-electron oxidation.
• Oxazole linkers show significant potential for peptide screening platforms, such as peptide-encoded libraries.