The neuropeptide Y receptor (YR), a rhodopsin-like G protein-coupled receptor (GPCR) and the hormone pancreatic polypeptide (PP) are members of the neuropeptide Y family consisting of four receptors (YR, YR, YR, YR) and three highly homologous peptide ligands (neuropeptide Y, peptide YY, PP). In this family, the YR is of particular interest as it is the only subtype with high affinity to PP over NPY. The YR, as a mediator of PP signaling, has a pivotal role in appetite regulation and energy homeostasis, offering potential avenues for the treatment of metabolic disorders such as obesity. PP as anorexigenic peptide is released postprandial from the pancreas in response to food intake, induces satiety signals and contributes to hamper excessive food intake. Moreover, this system was also described to be associated with different types of cancer: overexpression of YR have been found in human adenocarcinoma cells, while elevated levels of PP are related to the development of pancreatic endocrine tumors. The pharmacological relevance of the YR advanced the search for potent and selective ligands for this receptor subtype, which will be significantly progressed through the elucidation of the active state PP-YR cryo-EM structure. This review summarizes the development of novel PP-derived ligands, like Obinepitide as dual YR/YR agonist in clinical trials or UR-AK86c as small hexapeptide agonist with picomolar affinity, as well as the first allosteric modulators that selectively target the YR, VU0506013 as potent YR positive allosteric modulator or -VU0637120 as allosteric antagonist. This review provides valuable insights into the complex physiological functions of the YR and PP and the pharmacological relevance of the system in appetite regulation to open up new avenues for the development of tool compounds for targeted therapies with potential applications in metabolic disorders.

中文翻译：

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从结构、功能和治疗角度阐明神经肽 Y4 受体及其配体胰多肽

神经肽 Y 受体 (YR)、视紫红质样 G 蛋白偶联受体 (GPCR) 和激素胰多肽 (PP) 是神经肽 Y 家族的成员，该家族由四种受体（YR、YR、YR、YR）和三种受体组成。高度同源的肽配体（神经肽Y、肽YY、PP）。在这个家族中，YR 特别令人感兴趣，因为它是唯一与 PP 的亲和力高于 NPY 的亚型。YR 作为 PP 信号传导的介质，在食欲调节和能量稳态中发挥着关键作用，为治疗肥胖等代谢性疾病提供了潜在途径。PP 作为厌食肽，在餐后响应食物摄入而从胰腺释放，诱导饱腹感信号并有助于阻止过量食物摄入。此外，该系统还被描述为与不同类型的癌症相关：在人类腺癌细胞中发现了 YR 的过度表达，而 PP 水平的升高与胰腺内分泌肿瘤的发展有关。YR 的药理学相关性促进了对该受体亚型的有效和选择性配体的寻找，这将通过活性态 PP-YR 冷冻电镜结构的阐明而取得显着进展。本综述总结了新型 PP 衍生配体的开发，例如临床试验中作为双重 YR/YR 激动剂的 Obinepitide 或作为具有皮摩尔亲和力的小六肽激动剂的 UR-AK86c，以及第一个选择性靶向 YR 的变构调节剂 VU0506013有效的 YR 正变构调节剂或 -VU0637120 作为变构拮抗剂。本综述对 YR 和 PP 的复杂生理功能以及该系统在食欲调节中的药理学相关性提供了宝贵的见解，为开发用于靶向治疗的工具化合物开辟了新途径，并在代谢紊乱方面具有潜在的应用。