Abstract
The cyclic dimeric peptide 1229U91 (GR231118) has an unusual structure and displays potent, insurmountable antagonism of the Y1 receptor. To probe the structural basis for this activity, we have prepared ring size variants and heterodimeric compounds, identifying the specific residues underpinning the mechanism of 1229U91 binding. The homodimeric structure was shown to be dispensible, with analogues lacking key pharmacophoric residues in one dimer arm retaining high antagonist affinity. Compounds 11d-h also showed enhanced Y1R selectivity over Y4R compared to 1229U91.
Highlights
Neuropeptide Y (1, NPY) and its endocrine homologs peptide YY (PYY) and pancreatic polypeptide (PP) are 36-amino acid C-terminal amidated peptides with diverse physiological functions
In this work we have characterised a series of cyclic 1229U91 dimeric derived peptides at the Y1R and the Y4R in order to investigate the role of the cyclic structure in receptor recognition and selectivity
In addition to the role of the cyclic moiety, we have successfully investigated the role of the single dimer arm residues in Y1R and Y4R
Summary
Neuropeptide Y (1, NPY) and its endocrine homologs peptide YY (PYY) and pancreatic polypeptide (PP) are 36-amino acid C-terminal amidated peptides with diverse physiological functions. The development of peptide ligands was initiated by the discovery that the C-terminal NPY decapeptide, Tyr-Ile-Asn-Leu-Ile-Tyr-Arg-LeuArg-Tyr-NH2, possessed Y1R antagonist properties,[14] with structure-activity relationship (SAR) studies confirming that, for the native NPY peptide, Arg[33], Arg[35] and Tyr[36] were essential for receptor binding and biological activity of this analogue Based on this sequence, the subsequent peptide, BVD15 (4, BW1911U90; Ile-Asn-Pro-Ile-Tyr-Arg-Leu-Arg-Tyr-NH2; Figure 1), showed increased Y1R selectivity over the Y2R by 40 fold,[14,15] and has since been used as the basis for DOTA, NOTA and 18F radiolabelled derivatives.[16,17,18,19].
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
