title: Glyco-scan: varying glycosylation in the sequence of the peptide hormone PYY3-36 and its effect on receptor selectivity.
abstract: The increasing prevalence of obesity worldwide calls for safe and highly efficacious satiety drugs. PYY3-36 has been implicated in food intake regulation, and novel peptide analogues with high Y2 receptor-subtype selectivity and potency have potential as drugs for the treatment of obesity. It has been hypothesized that PYY3-36 associates with the plasma membrane prior to receptor activation such that the amphipathic alpha-helix of PYY3-36 possibly guides the C-terminal pentapeptide into the correct conformation for receptor activation. Ala-scans are used routinely to study the effect of individual amino acids in a given peptide sequence. Here we report the glyco-scan of the peptide hormone PYY3-36, in which hydroxyl side-chain functionalities were glycosylated; in addition new glycosylation sites were introduced. An array of novel PYY3-36 analogues with a glycan positioned in the water-membrane interface or in the N terminal were screened for Y-receptor affinity and selectivity as well as metabolic stability. Interestingly, in contrast to the Y1 and Y4 receptors, the Y2 receptor readily accommodated glycosylations. Especially glycosylations in the alpha-helical region of PYY3-36 were favorable both in terms of Y-receptor selectivity and endopeptidase resistance. We thus report several PYY3-36 analogues with enhanced Y-receptor selectivity. Our results can be used in the design of novel PYY analogues for the treatment of obesity. The glyco-scan concept, as systematically demonstrated here, has the potential for a wider applicability.
authors.affiliation: IGM, Faculty of Life Sciences, University of Copenhagen, Thorvaldsensvej 40, 1871 Frederiksberg C, Denmark.
authors.forename: Søren L
authors.initials: SL
authors.lastname: Pedersen
authors.forename: Catharina
authors.initials: C
authors.lastname: Steentoft
authors.forename: Niels
authors.initials: N
authors.lastname: Vrang
authors.forename: Knud J
authors.initials: KJ
authors.lastname: Jensen
mesh_terms: D000818:Animals; D002942:Circular Dichroism; D006031:Glycosylation; D006801:Humans; D051379:Mice; D009765:Obesity / Q000188:drug therapy; D010446:Peptide Fragments; D019894:Peptide YY / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D017433:Protein Structure, Secondary; D017476:Receptors, Neuropeptide Y / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D010446:Peptide Fragments; D017476:Receptors, Neuropeptide Y; C097212:neuropeptide Y-Y1 receptor; C095889:neuropeptide Y2 receptor; D019894:Peptide YY; C061785:peptide YY (3-36); C109491:neuropeptide Y4 receptor