Late-Stage Tryptophan Modification of Native Peptides through Photochemical Indole-to-Quinazoline Editing

Area of Science:

• Chemical Biology
• Organic Chemistry
• Medicinal Chemistry

Background:

• Site-specific late-stage modification of peptides is crucial for generating analogues of bioactive peptides.
• Skeletal editing presents a novel approach for developing advanced peptide modification techniques.

Purpose of the Study:

• To develop a facile tryptophan-specific late-stage peptide modification method.
• To apply this method for modifying peptide drugs and exploring its broad scope.

Main Methods:

• Photocatalytic indole-to-quinazoline editing of tryptophan residues.
• Application to both linear and cyclic peptide substrates.
• Modification of commercially available peptide drugs.

Main Results:

• A broad scope of peptide substrates was successfully modified.
• The method was effective in modifying existing peptide drugs.
• A proposed mechanism involving singlet oxygen oxidation and ammonia addition was elucidated.

Conclusions:

• The developed method provides an efficient and cost-effective strategy for late-stage peptide modification.
• This tryptophan-specific photocatalytic editing expands the toolkit for peptide analogue generation.
• The approach holds promise for the development of new peptide-based therapeutics.