Peptide-directed solid-phase reductive amination.

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Biochemistry

Background:

• Peptide-based therapeutics offer great potential but often suffer from poor stability.
• Modifying the peptide backbone, specifically replacing amide bonds, can enhance stability and bioavailability.
• Developing efficient and versatile methods for backbone modification is crucial for peptide drug design.

Purpose of the Study:

• To develop an integrated solid-phase strategy for synthesizing peptides containing the aminomethylene (Ψ[CH2-NH]) amide isostere.
• To enable the selective replacement of native amide bonds within peptide sequences.
• To create peptide fragments compatible with further synthesis and modification.

Main Methods:

• An integrated solid-phase reductive amination and solid-phase fragment condensation (SPFC) approach was employed.
• N-Fmoc-protected C-terminal peptide α-amino aldehydes were synthesized and condensed with peptide sequences on 2-chlorotrityl chloride (CLTR) resin.
• Imine reduction under mild conditions followed by mild acidic cleavage from the resin was performed.

Main Results:

• The methodology successfully replaced native amide bonds with Ψ[CH2-NH] linkages in peptide sequences.
• Epimerization at the reacting α-amino aldehyde was minimal, typically between 1-7%.
• The synthesized peptide fragments containing the Ψ[CH2-NH] linkage were compatible with subsequent peptide synthesis strategies.

Conclusions:

• The developed strategy provides a general and versatile tool for selective peptide backbone modification.
• This approach facilitates the creation of peptides and peptidomimetics with potentially improved properties.
• The methodology is relevant for advancing drug design through the development of more stable and effective peptide-based agents.