Use of homoserinyl γ-aldehyde-containing peptides in solid-phase reductive amination

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Peptide Chemistry

Background:

• Reduced peptide bonds (Ψ[CH2-NH]) are valuable isosteres in drug discovery.
• Solid-Phase Synthesis (SPS) and Solid-Phase Fragment Condensation (SPFC) are key for complex peptide construction.

Purpose of the Study:

• To develop a Solid-Phase Synthesis (SPS) strategy for peptides containing selectively deprotected homoserine (Hse) residues.
• To investigate the instability of Hse-derived γ-aldehyde intermediates and develop stabilization methods.
• To demonstrate the utility of stabilized Hse-γ-aldehydes in forming reduced peptide bonds via solid-phase reductive amination.

Main Methods:

• Selective side-chain deprotection of homoserine (Hse) residues during SPS.
• Solution-phase oxidation of Hse hydroxyl groups to γ-aldehydes.
• Systematic examination of intermediate instability and development of stabilization strategies.
• Solid-phase reductive amination for peptide ligation.

Main Results:

• Successfully synthesized peptides with selectively deprotected Hse residues.
• Identified and characterized the instability of Hse-γ-aldehyde intermediates, primarily due to cyclization.
• Developed effective stabilization strategies for these reactive intermediates.
• Demonstrated the efficient formation of Hse-β-Ψ[CH2-NH] reduced peptide bonds using the stabilized aldehydes.

Conclusions:

• The developed approach provides a versatile platform for synthesizing reduced peptide bonds.
• This method facilitates broader peptide ligation and modification strategies in drug discovery and development.
• Stabilized homoserinyl γ-aldehydes are key intermediates for efficient peptide bond construction.