An Efficient Thiol-ene Mediated Protocol for Thiolated Peptide Synthesis and On-Resin Diversification

Area of Science:

• Organic Chemistry
• Peptide Chemistry
• Chemical Biology

Background:

• The sulfhydryl group's reactivity is valuable for peptide modification, including macrocyclization, ligation, and bioconjugation.
• Existing methods for introducing thiol residues can be limited in scope or require complex procedures.

Purpose of the Study:

• To demonstrate a novel sequential acyl-thiol-ene/S-deacetylation protocol for on-resin installation of thiol residues onto bioactive peptides.
• To introduce a versatile fluorescent labeling strategy for direct on-resin conjugation.
• To provide a robust platform for peptide macrocyclization and bioconjugation.

Main Methods:

• Sequential acyl-thiol-ene reaction followed by S-deacetylation for thiol installation on-resin.
• Strategic placement of unsaturated residues to enable hydrothiolation/S-deacetylation.
• Development of a fluorescent labeling method for direct conjugation without purification.

Main Results:

• Selective installation of thiol residues onto bioactive peptides on-resin was achieved.
• The protocol facilitates the synthesis of disulfide-containing peptides with varying ring sizes for structure-activity relationship studies.
• A new fluorescent labeling strategy enables direct on-resin conjugation, simplifying the process.

Conclusions:

• The developed protocol offers a novel and efficient synthetic strategy for peptide macrocyclization and bioconjugation.
• This platform has broad applications in peptide synthesis and chemical biology research.
• The methods provide enhanced versatility for creating diverse peptide structures.