Rational Design of Peptidomimetics for Class B GPCRs: Potent Non-Peptide GLP-1 Receptor Agonists
Rational Design of Peptidomimetics for Class B GPCRs: Potent Non-Peptide GLP-1 Receptor Agonists
复制标题
DOI：
10.1007/978-0-387-73657-0_55
复制
发表时间：
2009-01-01
期刊：
影响因子：
--
通讯作者：
Beinborn, Martin
中科院分区：
文献类型：
--
作者：
Ahn, Jung-Mo;Han, Sun-Young;Beinborn, Martin
B类G蛋白偶联受体家族包括促胰液素、高血糖素、胰高血糖素样肽-1(GLP-1)、血管活性肠肽(VIP)、甲状旁腺激素(PTH)、垂体腺苷环化酶激活肽(PACAP)、胃抑制多肽(GIP)、促肾上腺皮质激素释放因子(CRF)等多肽的同源受体。虽然A类GPCRs识别小得多的配体，如多巴胺、生长抑素和脑啡肽，主要是利用跨膜区和膜附近的细胞外环上的残基，但所有B类GPCRs都具有相当长的N端链和大的细胞外环，形成多个结合口袋来容纳它们的大配体[1，2]。所有这些B类多肽在人体生理中发挥着独特的关键功能，被发现对许多疾病具有吸引力[2]。例如，高血糖素、GLP-1和GIP参与了葡萄糖的稳态，是治疗2型糖尿病和肥胖症的潜在新疗法[3]。降钙素和甲状旁腺素调节骨转换和钙稳态，有效治疗骨质疏松症[4]。CRF是人体对压力反应的主要媒介，有可能治疗焦虑和抑郁[5]。尽管它们都有很高的前景，但它们都很难在体内使用，因为它们容易迅速酶降解，而且不能口服。虽然配体筛选方法和从头设计已导致许多A类GPCRs的合成小分子(激动剂和拮抗剂)的鉴定，但这一策略在应用于B类受体时被证明不太成功。事实上，通过高通量筛选B类GPCRs确定的大多数非肽配体没有功能活性，因此被归类为拮抗剂[2]。用X-射线结晶学和核磁共振波谱研究了B类GPCRs的多肽配体的结构，发现其中许多具有高度螺旋结构。此外，在受体存在的情况下进行的生物物理研究也证明了多肽中α螺旋的生理意义。因此，我们选择了一种不同于传统筛选活动的方法，开发了针对B类GPCRs的α-螺旋模拟物，特别是GLP-1受体。
The family of class B G-protein coupled receptors (GPCRs) includes cognate receptors for peptide hormones like secretin, glucagon, glucagon-like peptide-1 (GLP-1), vasoactive intestinal peptide (VIP), parathyroid hormone (PTH), pituitary adenylate cyclase activating peptide (PACAP), gastric inhibitory polypeptide (GIP), corticotropin-releasing factor (CRF), and so on. Whereas class A GPCRs recognize much smaller ligands, such as dopamine, somatostatin, and enkephalins, by mostly using residues in transmembrane domains and extracellular loops proximal to membrane, all class B GPCRs possess significantly long N-terminal chains and large extracellular loops which constitute multiple binding pockets to host their large ligands [1, 2].All of these class B peptides play unique and critical functions in human physiology and are found to be attractive to treat many diseases [2]. For instance, glucagon, GLP-1 and GIP are involved in glucose homeostasis and are potential novel therapies for type 2 diabetes as well as obesity [3]. Calcitonin and PTH regulate bone turnover and calcium homeostasis and are effective to treat osteoporosis [4]. CRF is a principle mediator of the body’s response to stress and have the potential to treat anxiety and depression [5]. Despite their high promises, all of them have difficulty to be used in vivo since they are susceptible to rapid enzymatic degradation and not orally available. Whereas ligand screening approach and de novo design have led to the identification of synthetic small molecules (agonists and antagonists) for many class A GPCRs, this strategy has proven much less successful when applied to class B receptors. In fact, most of non-peptide ligands identified by high-throughput screening for class B GPCRs show no functional activity, thereby classified as antagonists [2]. Structures of peptide ligands for class B GPCRs have been investigated by X-ray crystallography and NMR spectroscopy, and many of them are found to adopt highly helical structures. In addition, physiological significance of α-helices in the peptides is also demonstrated by biophysical studies undertaken in the presence of receptors [6]. Thus, choosing a different approach than conventional screening campaigns, we have developed α-helix mimetics targeting class B GPCRs, especially GLP-1 receptor.