A switchable stapled peptide.

Area of Science:

• Peptide Chemistry
• Medicinal Chemistry
• Organic Synthesis

Background:

• O-N acyl transfer reactions are increasingly vital in peptide and medicinal chemistry.
• These reactions have enabled advancements in synthesizing complex peptides, including cyclic peptides and switchable peptide polymers.
• Efficient synthesis and purification of hydrophobic stapled peptides remain a challenge.

Purpose of the Study:

• To introduce a novel strategy for the synthesis and purification of hydrophobic stapled peptides.
• To explore the utility of an O-N acyl transfer-related reaction in peptide modification.
• To investigate the pH-dependent structural changes in a specifically designed stapled peptide.

Main Methods:

• Design and synthesis of a stapled peptide incorporating an O-N acyl transfer precursor.
• The staple linkage was formed via amide and ester bonds involving serine, diaminopropionic acid, and aspartic acid.
• Purification under acidic conditions where the serine α-amino group was protonated.

Main Results:

• Successful synthesis and purification of a hydrophobic stapled peptide.
• At physiological pH, the free amino group of serine initiated an O-N acyl shift.
• This shift reduced the staple length by one atom, resulting in a more hydrophobic peptide structure.

Conclusions:

• The developed strategy facilitates the synthesis and purification of hydrophobic stapled peptides.
• The O-N shift at physiological pH offers a mechanism for in-situ modification of peptide structure and properties.
• This approach provides a novel route to enhance peptide hydrophobicity for potential therapeutic applications.