Highly potent and small neuropeptide Y agonist obtained by linking NPY 1–4 via spacer to α‐helical NPY 25–36

Abstract

Analogues of neuropeptide Y (NPY) containing small N-and C-terminal segments linked via flexible spacer arms were found to exhibit receptor binding affinity constants almost as high as NPY as well as post-and presynaptic NPY-agonistic activities. One of the most active analogues contains N-terminal NPY segment 14 linked via e-aminocaproic acid (Aca) to the C-terminal partially a-helical peptide amide segment 25-36. NPY 14Aca-25-36 is the first highly potent NPY agonist, which is of considerably reduced size in comparison to the native hormone. The analogues are accessible by solid-phase synthesis using Fmoc strategy.

Structure/activity relationships of C‐terminal neuropeptide Y peptide segments and analogues composed of sequence 1–4 linked to 25–36

“…In conclusion, conformational dynamics studies on neuropeptide Y-(1 -4-Ahx-25 -36)-peptide support the assumption that the overall shape of neuropeptide Y-(1-4-Ahx-25 -36)-peptide, despite of the deletion of many loop residues and the introduction of a spacer, is still similar to the one proposed for neuropeptide Y [33], in particular with respect to the folding of the peptide chain.…”

“…Neuropeptide Y-(28 -32)-peptide is part of the amphiphilic a-helix [33]. To investigate the importance of this …”

“…From the X-ray structure of avian pancreatic polypeptide and from molecular dynamics simulations of neuropeptide Y [33] we designed analogues with N-terminal segments linked to the C-terminus. The derived molecular model indicates the N-terminal amino acids 1-4 to be close to the C-terminal peptide 25-31 of neuropeptide Y. Interactions of N-and Cterminus are also the result of other investigations [34 -361.…”

“…As Phe' and AcTyr' analogues are very active as well, the N-terminal aromatic ring seems to be mainly responsible for the increased activity. [33]. All dynamics simulations were calculated using the program DISCOVER (Biosym technologies, San Diego, USA) at constant temperature (300 K) and vacuum conditions.…”

Modified, cyclic dodecapeptide analog of neuropeptide Y is the smallest full agonist at the human Y2 receptor

“…So far, the 24-mer peptide NPY(13-36) is most frequently used for the testing of Y2 receptor mediated actions [4]. We and others have shown recently that smaller centrally or N-terminally truncated analogs such as [ NPY are full Y2 receptor agonists [9] or show at least good binding properties [12][13][14][15]. In addition, the L-Ala scan of NPY 1-36 suggests that only the C-terminal amino acids are involved in receptor binding and we speculated that the N-terminal residues only serve for the stabilization of the molecule [16].…”