Stapled truncated orexin peptides as orexin receptor agonists

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Karhu , L , Weisell , J , Turunen , P M , Leino , T O , Pätsi , H , Xhaard , H , Kukkonen , J P & Wallén , E A A 2018 , ' Stapled truncated orexin peptides as orexin receptor agonists ' , Peptides , vol. 102 , pp. 54-60 . https://doi.org/10.1016/j.peptides.2018.02.004

Title: Stapled truncated orexin peptides as orexin receptor agonists
Author: Karhu, Lasse; Weisell, Janne; Turunen, Pauli M.; Leino, Teppo O.; Pätsi, Henri; Xhaard, Henri; Kukkonen, Jyrki P.; Wallén, Erik A.A.
Contributor: University of Helsinki, Faculty of Pharmacy
University of Helsinki, University of Eastern Finland (UEF)
University of Helsinki, Medicum
University of Helsinki, Faculty of Pharmacy
University of Helsinki, Faculty of Pharmacy
University of Helsinki, Jyrki Kukkonen / Principal Investigator
University of Helsinki, Faculty of Pharmacy
Date: 2018-04
Language: eng
Number of pages: 7
Belongs to series: Peptides
ISSN: 0196-9781
URI: http://hdl.handle.net/10138/234577
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 amino acids.
Subject: peptide stapling
pseudopeptide
orexin
G protein-coupled receptor
OX1
BINDING
RECOGNITION
APPETITE
LIGANDS
ANALOGS
SYSTEM
ACID
Pseudopeptide
Peptide stapling
Orexin
3111 Biomedicine
317 Pharmacy
1182 Biochemistry, cell and molecular biology
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