Chemoselective Peptide Cyclization and Bicyclization Directly on Unprotected Peptides

Area of Science:

• Chemical Biology
• Organic Chemistry
• Peptide Chemistry

Background:

• Cyclic peptides are crucial modulators of biomolecular interactions.
• Efficient methods for constructing cyclic peptide libraries are needed for both peptide and non-peptide chemists.
• Current cyclization methods often require protection/deprotection steps, limiting their simplicity and scope.

Purpose of the Study:

• To develop a highly chemoselective and operationally simple method for direct cyclization of unprotected peptides.
• To explore the utility of ortho-phthalaldehyde (OPA) in forming novel cyclic peptide structures.
• To expand the capabilities for post-cyclization modification and bioconjugation.

Main Methods:

• Direct cyclization of unprotected peptides using ortho-phthalaldehyde (OPA).
• Reaction of OPA with lysine/N-terminus and cysteine residues in aqueous buffer.
• Integration with native chemical ligation for bicyclic peptide synthesis.
• One-pot functionalization of OPA-cyclized peptides with N-maleimide moieties.

Main Results:

• Successfully formed isoindole-bridged cyclic peptides from unprotected sequences.
• Demonstrated chemoselectivity, functional group tolerance, and operational simplicity in aqueous buffer.
• Achieved facile synthesis of bicyclic peptides by combining OPA cyclization with native chemical ligation.
• Enabled one-pot introduction of diverse functional motifs (fluorophores, glycans, peptides, DNA) onto cyclic peptides.

Conclusions:

• The OPA-mediated peptide cyclization offers a straightforward and versatile strategy for generating diverse cyclic peptides.
• This method simplifies the construction of cyclic peptide libraries and facilitates advanced bioconjugation.
• The OPA cyclization approach significantly broadens the synthetic toolbox for peptide chemists and bioconjugation applications.