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

IF 2.5 3区 医学 Q3 ENDOCRINOLOGY & METABOLISM
Corinna Schüß, Victoria Behr, Annette G. Beck-Sickinger
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引用次数: 0

摘要

神经肽 Y4 受体(Y4R)是一种类似于荷尔蒙的 G 蛋白偶联受体(GPCR),与激素胰多肽(PP)同属于神经肽 Y 家族,该家族由四种受体(Y1R、Y2R、Y4R、Y5R)和三种高度同源的肽配体(神经肽 Y、肽 YY、PP)组成。在这个家族中,Y4R 尤为引人关注,因为它是唯一一个与 PP 的亲和力高于 NPY 的亚型。Y4R 作为 PP 信号转导的介质,在食欲调节和能量平衡中起着关键作用,为治疗肥胖等代谢性疾病提供了潜在的途径。PP 作为一种厌食肽,在摄入食物后会从胰腺释放,诱导饱腹感信号,有助于抑制过多的食物摄入。此外,该系统还被描述为与不同类型的癌症有关:在人类腺癌细胞中发现了 Y4R 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。Y4R 的药理相关性推动了对该受体亚型的强效和选择性配体的研究,通过阐明活性状态 PP-Y4R 的低温电子显微镜结构,这一研究将取得重大进展。本综述总结了新型 PP 衍生配体的开发情况,如正在进行临床试验的 Y2R/Y4R 双激动剂 Obinepitide 或具有皮摩尔亲和力的小型六肽激动剂 UR-AK86c,以及首批选择性靶向 Y4R 的异构调节剂,如强效 Y4R 阳性异构调节剂 VU0506013 或异构拮抗剂 (S)-VU0637120。在此,我们对 Y4R 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出了宝贵的见解,为开发具有代谢紊乱潜在应用价值的靶向治疗工具化合物开辟了新的途径。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Illuminating the neuropeptide Y4 receptor and its ligand pancreatic polypeptide from a structural, functional, and therapeutic perspective

Illuminating the neuropeptide Y4 receptor and its ligand pancreatic polypeptide from a structural, functional, and therapeutic perspective

The neuropeptide Y4 receptor (Y4R), 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 (Y1R, Y2R, Y4R, Y5R) and three highly homologous peptide ligands (neuropeptide Y, peptide YY, PP). In this family, the Y4R is of particular interest as it is the only subtype with high affinity to PP over NPY. The Y4R, 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 Y4R 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 Y4R 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-Y4R cryo-EM structure. This review summarizes the development of novel PP-derived ligands, like Obinepitide as dual Y2R/Y4R 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 Y4R, e.g. VU0506013 as potent Y4R positive allosteric modulator or (S)-VU0637120 as allosteric antagonist. Here, we provide valuable insights into the complex physiological functions of the Y4R 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.

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来源期刊
Neuropeptides
Neuropeptides 医学-内分泌学与代谢
CiteScore
5.40
自引率
6.90%
发文量
55
审稿时长
>12 weeks
期刊介绍: The aim of Neuropeptides is the rapid publication of original research and review articles, dealing with the structure, distribution, actions and functions of peptides in the central and peripheral nervous systems. The explosion of research activity in this field has led to the identification of numerous naturally occurring endogenous peptides which act as neurotransmitters, neuromodulators, or trophic factors, to mediate nervous system functions. Increasing numbers of non-peptide ligands of neuropeptide receptors have been developed, which act as agonists or antagonists in peptidergic systems. The journal provides a unique opportunity of integrating the many disciplines involved in all neuropeptide research. The journal publishes articles on all aspects of the neuropeptide field, with particular emphasis on gene regulation of peptide expression, peptide receptor subtypes, transgenic and knockout mice with mutations in genes for neuropeptides and peptide receptors, neuroanatomy, physiology, behaviour, neurotrophic factors, preclinical drug evaluation, clinical studies, and clinical trials.
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