Stapled truncated orexin peptides as orexin receptor agonists

Area of Science:

• Neuroscience
• Peptide Chemistry
• Structural Biology

Background:

• Orexin-A and orexin-B are endogenous agonists for orexin receptors.
• Orexin peptides are suggested to bind in an alpha-helical conformation.
• Truncation of orexin peptides affects their activity and potency.

Purpose of the Study:

• To stabilize the alpha-helical conformation of orexin-A15-33 using peptide stapling.
• To investigate the role of alpha-helical structure in orexin receptor activation.
• To explore the impact of structural modifications on peptide potency and activity.

Main Methods:

• Peptide stapling was employed to stabilize the alpha-helical structure of orexin-A15-33 at four distinct sites.
• Variations in cross-linker length and amino acid substitutions (alpha-aminoisobutyric acid) were introduced at a hinge region.
• Modifications were strategically avoided near the C-terminus, crucial for activity.

Main Results:

• Central and N-terminal modifications resulted in bioactive peptides, indicating successful stabilization of helical structure.
• Modified peptides exhibited decreased potencies compared to the native peptide.
• The findings suggest that orexin receptors can accommodate and be activated by alpha-helical peptides.

Conclusions:

• The study provides evidence that alpha-helical conformations of orexin peptides can activate orexin receptors.
• Reduced potency in modified peptides may be due to stabilized suboptimal conformations or blocked receptor interactions.
• Peptide stapling is a viable strategy for studying the structure-activity relationships of orexin peptides.