Direct Fmoc-chemistry-based solid-phase synthesis of peptidyl thioesters

Area of Science:

• Organic Chemistry
• Biochemistry
• Synthetic Chemistry

Background:

• Solid-phase peptide synthesis (SPPS) is a cornerstone of modern biochemistry.
• Current methods often face challenges in releasing peptides in specific functional forms.
• The development of novel linker strategies is crucial for expanding SPPS applications.

Purpose of the Study:

• To develop a new method for Fmoc-SPPS compatible with thioester formation.
• To investigate the utility of a thioglycinamide linker for peptide release.
• To enable the synthesis of C-terminal thioesters for further bioconjugation.

Main Methods:

• Attachment of a growing peptide chain to a glycylaminomethyl resin via a thioglycinamide bond.
• Utilizing Fmoc-chemistry for solid-phase peptide synthesis.
• S-alkylation of the thioamide to form a thioimide.
• Cleavage from the resin using aqueous trifluoroacetic acid.

Main Results:

• The thioglycinamide linkage is compatible with Fmoc-SPPS.
• S-alkylation successfully converts the thioamide to a thioimide.
• Treatment with trifluoroacetic acid efficiently releases the peptide as a C-terminal thioester.
• The method provides a reliable route to thioester-functionalized peptides.

Conclusions:

• This novel Fmoc-compatible strategy enables the efficient synthesis of peptides with C-terminal thioesters.
• The released thioesters are suitable for subsequent bioconjugation reactions.
• This method expands the toolkit for peptide synthesis and modification.