Stapled truncated orexin peptides as orexin receptor agonists

Peptides
Lasse KarhuErik A A Wallén

Abstract

The peptides orexin-A and -B, the endogenous agonists of the orexin receptors, have similar 19-amino-acid C-termini which retain full maximum response as truncated peptides with only marginally reduced potency, while further N-terminal truncations successively reduce the activity. The peptides have been suggested to bind in an α-helical conformation, and truncation beyond a certain critical length is likely to disrupt the overall helical structure. In this study, we set out to stabilize the α-helical conformation of orexin-A15-33 via peptide stapling at four different sites. At a suggested hinge region, we varied the length of the cross-linker as well as replaced the staple with two α-aminoisobutyric acid residues. Modifications close to the peptide C-terminus, which is crucial for activity, were not allowed. However, central and N-terminal modifications yielded bioactive peptides, albeit with decreased potencies. This provides evidence that the orexin receptors can accommodate and be activated by α-helical peptides. The decrease in potency is likely linked to a stabilization of suboptimal peptide conformation or blocking of peptide backbone-receptor interactions at the hinge region by the helical stabilization or the modified ...Continue Reading

Citations

Sep 28, 2018·PloS One·Jordan D LewickyHoang-Thanh Le
Jun 5, 2020·Nature Reviews. Drug Discovery·Anthony P DavenportJanet J Maguire
Feb 23, 2019·The Journal of Physical Chemistry. B·Lasse KarhuHenri Xhaard

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