Bioorthogonal Peptide Macrocyclization Using Oxime Ligation.

Area of Science:

• Biochemistry
• Organic Chemistry
• Medicinal Chemistry

Background:

• Constrained peptide synthesis is crucial for developing potent therapeutics but remains challenging.
• Oxime ligation is a bioorthogonal method commonly employed in protein bioconjugation.

Purpose of the Study:

• To develop a straightforward method for synthesizing constrained peptides using standard solid-phase peptide synthesis.
• To demonstrate the facile preparation of conformationally constrained protease inhibitors.

Main Methods:

• Installation of N-terminal ketones and aminooxy side chains during solid-phase peptide synthesis.
• Spontaneous cyclization of peptides upon acidic cleavage or in aqueous buffer.
• Synthesis and activity testing of protease inhibitors with varying degrees of conformational constraint.

Main Results:

• A facile method for installing ketone and aminooxy functionalities for peptide cyclization was established.
• Spontaneous cyclization was achieved under mild conditions (acidic cleavage or aqueous buffer).
• The most conformationally constrained protease inhibitor synthesized showed a 100-fold increase in activity compared to its linear counterpart.

Conclusions:

• The developed method simplifies the synthesis of constrained peptides.
• This technique facilitates the creation of highly active protease inhibitors.
• The findings offer a promising strategy for peptide-based drug discovery.