Design and Synthesis of Peptide YY Analogues with C-terminal Backbone Amide-to-Ester Modifications

Louise Albertsen; Julie J Andersen; Johan F Paulsson; Jens K Thomsen; Jens C Norrild; Kristian Strømgaard

doi:10.1021/ml400335g

Design and Synthesis of Peptide YY Analogues with C-terminal Backbone Amide-to-Ester Modifications

ACS Med Chem Lett. 2013 Oct 21;4(12):1228-32. doi: 10.1021/ml400335g. eCollection 2013 Dec 12.

Authors

Louise Albertsen¹, Julie J Andersen¹, Johan F Paulsson², Jens K Thomsen², Jens C Norrild², Kristian Strømgaard³

Affiliations

¹ 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.
² Departments of Protein & Peptide Chemistry, Diabetes NBEs & Obesity Biology, and Diabetes Biophysics, Novo Nordisk A/S , Novo Nordisk Park 1, DK-2760 Måløv, Denmark.
³ Department of Drug Design and Pharmacology, University of Copenhagen , Universitetsparken 2, DK-2100 Copenhagen, Denmark.

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.

Keywords: NPY; PYY; Peptide YY; amide-to-ester modifications; neuropeptide Y.