Ligation, Macrocyclization, and Simultaneous Functionalization of Peptides by Multicomponent Reactions (MCR)

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Peptide Chemistry

Background:

• Multicomponent reactions (MCRs) are increasingly utilized in solid-phase synthesis.
• Peptide cyclization and N-functionalization are crucial for drug development and bioconjugation.

Purpose of the Study:

• To develop a solid-phase compatible MCR strategy for peptide cyclization and N-functionalization.
• To demonstrate the utility of this method using Gramicidin S as a model.

Main Methods:

• Solid-phase synthesis.
• On-resin Ugi multicomponent reactions.
• Peptide cyclization and N-functionalization.

Main Results:

• A robust solid-phase strategy for simultaneous backbone N-functionalization and cyclization was established.
• Gramicidin S was successfully cyclized and N-functionalized on solid support.
• The method allows for the incorporation of conjugation handles or labels.

Conclusions:

• MCRs provide a powerful and efficient approach for solid-phase peptide derivatization.
• This strategy is valuable for creating complex peptide structures for pharmaceutical and biotechnological applications.