title: Design and Synthesis of Peptide YY Analogues with C-terminal Backbone Amide-to-Ester Modifications.
abstract: Peptide YY (PYY) is a gut hormone that activates the G protein-coupled neuropeptide Y (NPY) receptors, and because of its appetite reducing actions, it is evaluated as an antiobesity drug candidate. The C-terminal tail of PYY is crucial for activation of the NPY receptors. Here, we describe the design and preparation of a series of PYY(3-36) depsipeptide analogues, in which backbone amide-to-ester modifications were systematically introduced in the C-terminal. Functional NPY receptor assays and circular dichroism revealed that the ψ(CONH) bonds at positions 30-31 and 33-34 are particularly important for receptor interaction and that the latter is implicated in Y2 receptor selectivity.
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen , Universitetsparken 2, DK-2100 Copenhagen, Denmark ; Departments of Protein & Peptide Chemistry, Diabetes NBEs & Obesity Biology, and Diabetes Biophysics, Novo Nordisk A/S , Novo Nordisk Park 1, DK-2760 Måløv, Denmark.
authors.forename: Louise
authors.initials: L
authors.lastname: Albertsen
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen , Universitetsparken 2, DK-2100 Copenhagen, Denmark ; Departments of Protein & Peptide Chemistry, Diabetes NBEs & Obesity Biology, and Diabetes Biophysics, Novo Nordisk A/S , Novo Nordisk Park 1, DK-2760 Måløv, Denmark.
authors.forename: Julie J
authors.initials: JJ
authors.lastname: Andersen
authors.affiliation: Departments of Protein & Peptide Chemistry, Diabetes NBEs & Obesity Biology, and Diabetes Biophysics, Novo Nordisk A/S , Novo Nordisk Park 1, DK-2760 Måløv, Denmark.
authors.forename: Johan F
authors.initials: JF
authors.lastname: Paulsson
authors.affiliation: Departments of Protein & Peptide Chemistry, Diabetes NBEs & Obesity Biology, and Diabetes Biophysics, Novo Nordisk A/S , Novo Nordisk Park 1, DK-2760 Måløv, Denmark.
authors.forename: Jens K
authors.initials: JK
authors.lastname: Thomsen
authors.affiliation: Departments of Protein & Peptide Chemistry, Diabetes NBEs & Obesity Biology, and Diabetes Biophysics, Novo Nordisk A/S , Novo Nordisk Park 1, DK-2760 Måløv, Denmark.
authors.forename: Jens C
authors.initials: JC
authors.lastname: Norrild
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen , Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors.forename: Kristian
authors.initials: K
authors.lastname: Strømgaard
keywords: NPY; PYY; Peptide YY; amide-to-ester modifications; neuropeptide Y