BACKGROUND PYY (1-36) peptides from phylogenetically ancient fish, such as sea lamprey, have previously been shown to function as specific neuropeptide Y1 receptor (NPYR1) agonists. Although, sea lamprey PYY (1-36) is N-terminally stable, we reveal in this study that the peptide is subject to endopeptidase mediated C-terminal dipeptide degradation. In an attempt to prevent this, (d-Arg35)-sea lamprey PYY (1-36) was developed. METHODS In vitro bioassays assessed enzymatic stability, insulinostatic activity as well as beta-cell anti-apoptotic actions of (d-Arg35)-sea lamprey PYY (1-36). Follow-up studies examined the impact of twice daily administration of sea lamprey PYY (1-36) or (d-Arg35)-sea lamprey PYY (1-36) in multiple low dose STZ-induced diabetic mice. RESULTS (d-Arg35)-sea lamprey PYY (1-36) was fully resistant to plasma enzymatic degradation. The peptide possessed similar significant insulinostatic, as well as positive anti-apoptotic biological actions, as the parent peptide. Sea lamprey PYY (1-36) and (d-Arg35)-sea lamprey PYY (1-36) delayed diabetes progression in STZ mice. Both treatment interventions induced a significant decrease in body weight, food and fluid intake as well as glucose and glucagon concentrations. In addition, glucose tolerance, plasma and pancreatic insulin were partially normalised. (d-Arg35)-sea lamprey PYY (1-36) was significantly more effective than sea lamprey PYY (1-36) in terms of enhancing glucose-stimulate insulin release. Both treatments improved pancreatic islet morphology, linked to decreased apoptosis of beta-cells. CONCLUSION We present (d-Arg35)-sea lamprey PYY (1-36) as the first-in-class N- and C-terminally stable PYY (1-36) peptide analogue. GENERAL SIGNIFICANCE Enzymatically stable, long-acting PYY (1-36) peptides highlight the therapeutic benefits of sustained activation of NPYR1's in diabetes.

中文翻译：

---

肽能N和C端稳定的哺乳动物NPY1R激动剂的开发和表征，该激动剂可预防糖尿病的诱导。

背景技术先前已经显示，来自系统发育上古老的鱼类，例如海七lamp鱼的PYY（1-36）肽具有特定的神经肽Y1受体（NPYR1）激动剂的功能。尽管海七rey鳗PYY（1-36）在N端稳定，但我们在这项研究中发现该肽受内肽酶介导的C端二肽降解。为了防止这种情况，开发了（d-Arg35）-海七lamp鳗PYY（1-36）。方法体外生物测定评估了（d-Arg35）-海七rey鳗PYY（1-36）的酶稳定性，胰岛素抑制活性以及β细胞抗凋亡作用。后续研究检查了在多次低剂量STZ诱导的糖尿病小鼠中每天两次服用海七rey PYY（1-36）或（d-Arg35）-海七rey PYY（1-36）的影响。结果（d-Arg35）-海七lamp鳗PYY（1-36）完全抗血浆酶降解。该肽具有与母体肽相似的显着的胰岛素抑制作用以及积极的抗凋亡生物学作用。海七rey菜PYY（1-36）和（d-Arg35）-海七rey菜PYY（1-36）延迟了STZ小鼠的糖尿病进展。两种治疗干预均导致体重，食物和液体摄入量以及葡萄糖和胰高血糖素浓度显着降低。此外，葡萄糖耐量，血浆和胰腺胰岛素均已部分标准化。就增强葡萄糖刺激的胰岛素释放而言，（d-Arg35）-海七rey菜PYY（1-36）比海七rey菜PYY（1-36）更有效。两种治疗方法均能改善胰岛的形态，并与减少β细胞凋亡有关。结论我们提出了（d-Arg35）-海七lamp鳗PYY（1-36），作为同类中第一个N-和C-末端稳定的PYY（1-36）肽类似物。一般意义酶稳定的长效PYY（1-36）肽突出了NPYR1持续激活在糖尿病中的治疗益处。