2. Academic Validation
  3. Stapled truncated orexin peptides as orexin receptor agonists

Stapled truncated orexin peptides as orexin receptor agonists

  • Peptides. 2018 Apr;102:54-60. doi: 10.1016/j.peptides.2018.02.004.
Lasse Karhu 1,  Janne Weisell 2,  Pauli M Turunen 3,  Teppo O Leino 4,  Henri Pätsi 5,  Henri Xhaard 6,  Jyrki P Kukkonen 7,  Erik A A Wallén 8
Affiliations

Affiliations

  • 1 Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, POB 56, FI-00014 University of Helsinki, Finland. Electronic address: [email protected].
  • 2 School of Pharmacy, University of Eastern Finland, POB 1627, FI-70211 Kuopio, Finland. Electronic address: [email protected].
  • 3 Biochemistry and Cell Biology, Department of Veterinary Biosciences, Faculty of Veterinary Medicine, POB 66, FI-00014, University of Helsinki, Finland; Department of Physiology, Institute of Biomedicine, Biomedicum Helsinki, POB 63, FI-00014 University of Helsinki, Finland. Electronic address: [email protected].
  • 4 Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, POB 56, FI-00014 University of Helsinki, Finland. Electronic address: [email protected].
  • 5 Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, POB 56, FI-00014 University of Helsinki, Finland. Electronic address: [email protected].
  • 6 Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, POB 56, FI-00014 University of Helsinki, Finland. Electronic address: [email protected].
  • 7 Biochemistry and Cell Biology, Department of Veterinary Biosciences, Faculty of Veterinary Medicine, POB 66, FI-00014, University of Helsinki, Finland; Department of Physiology, Institute of Biomedicine, Biomedicum Helsinki, POB 63, FI-00014 University of Helsinki, Finland. Electronic address: [email protected].
  • 8 Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, POB 56, FI-00014 University of Helsinki, Finland. Electronic address: [email protected].
PMID: 29475074 DOI: 10.1016/j.peptides.2018.02.004
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.

Keywords

G protein-coupled receptor; Orexin; Peptide stapling; Pseudopeptide.

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