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Glu³⁰ 赖氨酸-内酰胺桥将astressin限制在α-螺旋构象中，这似乎是其特别高的CRF拮抗剂活性的原因。Astressin在体外抑制ACTH分泌的效力是α-螺旋CRF（9-41）的100倍，在体内的效力是迄今为止报道的任何其他CRF拮抗剂的10倍以上。

The Glu³⁰ to Lys³³ lactam bridge constrains astressin in an α-helical conformation which seems to be responsible for its especially high CRF antagonist activity. Astressin is 100 times more potent than α-helical CRF (9-41) at inhibiting ACTH secretion in vitro, and more than 10 times more potent in vivo than any other CRF antagonist reported to date.

一种新的CRF拮抗剂（cyclo（30/33），当以低剂量（1-10ug）注射到CSF中时，会导致对CRF的拮抗作用和胃肠运动功能的应激相关改变，而在这些体内没有内在作用系统。

A new CRF antagonist (cyclo(30/33) that, when injected into the CSF at low doses (1-10ug), results in antagonistic action against CRF and stress-related alterations of gastrointestinal motor function, without an intrinsic effect in these in vivo systems.

Definition
Corticotropin-releasing factor (CRF) represents an early chemical signal of the stress response and activates the hypothalamus–pituitary–adrenal axis in response to a stressful stimulus.

Discovery
The existence of CRF was first proposed in 1955 by Guillemin and Rosenberg and Saffran and Schally. Initially isolated from ovine hypothalamus and characterized as a 41 amino acidpeptide in 1981, CRF was subsequently characterizedfrom rat hypothalami, and the identical structure was deduced for human CRF on the basis of the cDNA sequence of the human CRF precursor gene 1,2. Eckart K et al., in 2001 developed strategies permitting synthesis of CRF analogs for CRFBP or CRFR without cross-reaction. They found that one residue of the ARAE motif served as a switch enhancing or preventing ligand binding to CRFBP. This knowledge was applied to the development of peptidic CRF agonists and antagonists 3.

Structural Characteristics
CRF is a 41- amino acid peptide, was originally isolated from the hypothalamus. The stretch of amino acid residues 22–25, Ala-Arg-Ala-Glu, of human/rat CRF, representing the ARAE motif, was found to be responsible for the high affinity of hyrCRF to CRFBP, in contrast to the low affinity of ovine CRF containing the sequence Thr-Lys-Ala-Asp instead. Interestingly, each residue of the ARAE sequence contributed to the high affinity of hyrCRF, as was demonstrated by single residue exchanges. Although sauvagine (Svg), another peptide of the CRF peptide family, binds to CRFBP with only low affinity, the Svg analog containing the ARAE sequence, instead of Glu21-Lys22-Gln23-Glu24, binds with high affinity. However, it has not yet been investigated whether all residues of the ARAE motif are important  4,5.  Specific modifications and substitutions of CRF that led to the discovery of antagonists with extended duration of action as compared to that of astressin {cyclo(30−33)[dPhe12,Nle21,Glu30,Lys33,Nle38]hCRF(12-41)}. These additional modifications included elongation of the peptide chain by three residues at the N-terminus, its acetylation, and the [CαMeLeu27] substitution to yield cyclo(30−33)[dPhe12, Nle21,CαMeLeu27,Glu30,Lys33,Nle38]Ac-hCRF(9-41), which was found to be longer acting than astressin which further increases the efficiency (potency, duration of action, and bioavailability) of this family of antagonists 6. 

Mode of Action
CRF exhibits its biologic actions through G rotein-dependent receptors. To date, mainly two subtypes of CRF receptors (CRFRs), CRFR1 and CRFR2, have been identified. The central actions of CRF-like peptides are also modulated by the water-soluble CRF binding protein (CRFBP). Consistent with the results of experiments on CRFBP deficient mice, the physiological role of endogenous CRFBP in the central nervous system limit the availability of free ligand for CRFR-mediated actions in brain regions where CRFBP, CRFR, and CRF are colocalized. In addition, central injection of CRF antagonists such as a-helical CRF9–41 (a-hel-CRF9–41), which are bound by CRFBP with high affinity, release endogenous CRF by displacement from CRFBP. The CRF antagonist anti-Svg-30 (aSvg-30) is selective for CRFR2 and useful in in vivo experiments because of its high solubility in cerebrospinal fluid (CSF), the antagonists a-hel-CRF9–41 and Ast are not selective, and bind with different affinities to CRFBP, CRFR1, and CRFR2 7,8.

Functions

Homeostasis, CRF plays a major role in the maintenance or restoration of homeostasis by stimulating the activity of the hypothalamic-pituitary-adrenal (HPA) axis.

Biological function, it also acts within the brain to control immune, reproductive and cardiovascular functions as well as catecholamine release, drug withdrawal, behavior, mood, and anxiety thereby implicating CRF not only as central mediator of stress responses, but also in a variety of stress srelated or -unrelated peripheral functions 9.

On central nervous system, CRF mediates the hypothalamic-pituitary-adrenocortical stress axis. CRF was later found to be widely distributed also outside the hypothalamus throughout the central nervous system 8.

Neurotransmitter, CRF functions as a neurotransmitter or neuromodulator eliciting a wide spectrum of autonomic, electrophysiological, and behavioral effects.

Peripheral sites,  in addition to pituitary and central nervous system effects, some effects of CRF in vitro and in vivo have been found at various peripheral sites, where specific binding sites for CRF or messenger RNA (mRNA) for CRF receptors have been localized as well 1.

References

1.     Guillemin R, Rosenberg B (1955). Humoral hypothalamic control of anterior pituitary: a study with combined tissue cultures. Endocrinology, 57:599-607.

2.     Shibahara S, Morimoto Y, Furutani Y, Notake M, Takahashi H, Shimizu S, Horikawa S, Numa S (1983). Isolation and sequence analysis of the human corticotropin-releasing factor precursor gene. Embo. J., 2(5):775-779.

3.     Eckart K, Jahn O, Radulovic J, Tezval H, van Werven L, Spiess J (2001). A single amino acid serves as an affinity switch between the receptor and the binding protein of corticotropin-releasing factor: Implications for the design of agonists and antagonists. PNAS., 98(20):11142-11147.

4.     Sutton SW, Behan DP, Lahrichi SL, Kaiser R, Corrigan A, Lowry P, Potter E, Perrin MH, Rivier J, Vale WW (1995). Ligand requirements of the human corticotropin-releasing factor-binding protein. Endocrinology, 136(3):1097-1102.

5.     Jahn O, Eckart K, Sydow S, Hofmann BA, Spiess J (2001). Pharmacological characterization of recombinant rat corticotropin releasing factor binding protein using different sauvagine analogs.  Peptides, 22(1):47–56.

6.     Rivier JE, Kirby DA, Lahrichi SL, Corrigan A, Vale WW, Rivier CL (1999). Constrained corticotropin releasing factor antagonists (astressin analogues) with long duration of action in the rat. J. Med. Chem., 42(16):3175–3182.

7.     Spiess J, Dautzenberg FM, Sydow S, Hauger RL, Rühmann A, Blank T, Radulovic J  (1998). Molecular Properties of the CRF Receptor. Trends Endocrinol Metab., 9(4):140–145.

8.     Brauns O, Liepold T, Radulovic J, Spiess J (2001). Pharmacological and chemical properties of astressin, antisauvagine-30 and alpha-helCRF: significance for behavioral experiments.  Neuropharmacology, 41:507–516.
9.     Gulyas J, Rivier C, Perrin M, Koerber SC, Sutton S, Corrigan A, Lahrichi SL, Craig AG, Vale W, Rivier J  (1995). Potent, structurally constrained agonists and competitive antagonists of corticotropin-releasing factor. PNAS,. 92(23):10575-10579.

【拮抗剂多肽在癌症治疗中的作用机制】

       1 、抑制肿瘤细胞增殖：某些多肽能够直接作用于肿瘤细胞，干扰其增殖信号传导路径，从而抑制肿瘤细胞的增长。

       2 、诱导肿瘤细胞凋亡：多肽可以通过模拟肿瘤抑制蛋白或激活凋亡信号通路，促进肿瘤细胞走向程序性死亡。

       3 、免疫调节：多肽类化合物能够激活机体的免疫系统，增强免疫细胞对肿瘤细胞的识别和攻击能力，从而辅助控制肿瘤生长。

       4、阻断蛋白质相互作用：多肽可以设计成特定的结构，以阻断肿瘤细胞内部或肿瘤微环境中关键蛋白质的相互作用，这些相互作用对于肿瘤的生存和扩散至关重要。

       5、抑制肿瘤新生血管生成：多肽通过抑制血管内皮生长因子（VEGF）等促进血管生成的因子，切断肿瘤的血液供应，抑制肿瘤生长和转移。

       6 、靶向递送：多肽可以通过与其表面受体特异性结合，实现对肿瘤细胞的靶向递送，提高药物的疗效并减少对正常细胞的毒性。

定义
神经肽的长度为3-40个氨基酸，可作为神经递质。它们广泛分布于中枢神经系统和周围神经系统。

发现
神经肽是由约翰·休斯博士和科斯特里茨博士于1975年发现的。它们是内啡肽，内在产生的吗啡样物质，会在体内产生一系列类似药物的作用。可以从序列信息1中鉴定神经肽前体mRNA序列，并且得到的翻译蛋白序列包括信号肽序列和一个或多个神经肽。广泛而复杂的一系列酶处理步骤，包括被激素或前蛋白转化酶切割以及其他翻译后修饰，在创建活性神经肽之前就发生在翻译后的蛋白质序列上  2,3。

结构特征
通过核磁共振（NMR）光谱研究了几种来自软体动物的类似神经肽的构象性质。肽的N末端可变区中的氨基酸取代对溶液中反向转化的种群具有显着影响。通过使用两个独立的NMR参数测得的转弯数，发现使用Helix aspersa的受体膜制剂与IC50值高度相关（r2 = 0.93和0.82）。这些结果表明，构象集合降低了特定肽相对于特定受体4,5的有效浓度。

神经肽Y与人肽相同，并且与禽胰多肽高度同源。神经肽Y和禽胰多肽之间的同源性保留了维持三级结构必不可少的所有残基。结果表明，神经肽保留了紧凑的三级结构，其特征是在N末端的聚脯氨酸II类螺旋和C末端的a螺旋 6之间广泛的疏水相互作用。

已经通过许多孤儿受体之一发现了一些肽，这些受体是内源性配体未知的受体，例如“类阿片受体样1”（ORL1）。随后，已阐明该ORL1受体的内源性激动剂的结构，一种称为孤儿蛋白FQ或伤害感受蛋白的17个氨基酸的肽7。

行动方式
神经肽是由神经元作为细胞间信使释放的肽。一些神经肽充当神经递质，而另一些充当激素。神经肽既可以为我们提供支持，也可以为我们提供帮助。抗炎神经肽可帮助我们减少皮肤发炎。神经肽是自然产生的，可以在非常有限的时间内与靶细胞膜受体在明确的作用位点相互作用。因此，大多数这些内源性化合物的特征在于低的生物屏障渗透性和非常高的酶促降解敏感性。脑室内或全身注射神经肽Y（NPY）可使cast割的雌性大鼠血浆中的促黄体生成激素（LH）水平降低。6。

功能

生物功能，神经肽控制着我们的情绪，能量水平，痛苦和愉悦感，体重以及解决问题的能力；它们还会形成记忆，情感行为，食欲和发炎，修复疤痕和皱纹并调节我们的免疫系统。这些活跃的大脑小信使实际上打开了皮肤7的细胞功能。因此，今天，与神经肽系统相互作用的药物设计是后基因组药物化学研究最广泛的途径之一。

P物质已被确定为负责伤害性信号传递的主要神经肽。内源性阿片类药物是天然神经肽，负责伤害性信号的调节（通常是抑制）。

免疫系统，当它们被分泌时，它们会激活自然杀伤细胞（NK细胞），从而增强我们的免疫系统。

随着内啡肽的分泌越来越多，血管病变使收缩的血管恢复到正常状态，使血液以正常方式流动。大多数成人疾病都始于血管堵塞。内啡肽有助于改善血液循环。

内啡肽通过去除超氧化物具有抗衰老作用。从呼吸进入人体的氧气可以转变为超氧化物。这是造成人类疾病和衰老的最大敌人之一。

抗压力激素，应对压力的能力与我们体内的内啡肽水平成正比。

缓解疼痛的作用是，我们的神经系统在接收到疼痛信号时会分泌神经递质。一旦内啡肽在疼痛的那一刻被释放，内啡肽就会与神经元上的内啡肽受体结合，从而阻止第一种神经递质被分泌出来。

记忆力，神经肽可以改善记忆力，因为它们可以使脑细胞保持年轻健康。

参考

1.     Hummon AB, Richmond TA, Verleyen P, Baggerman G, Huybrechts J, Ewing MA, Vierstraete E, Rodriguez-Zas SL, Liliane SL, Robinson GE (2006). From the genome to the proteome: uncovering peptides in the Apis brain. Science, 27(314):647-649.

2.     Rockwell NC, Krysan DJ, Komiyama T, Fuller RS (2002). Precursor processing by Kex2/Furin Proteases. Chem. Rev., 102:4525–4548.

3.     Von ER, Beck-Sickinger AG (2004). Biosynthesis of peptide hormones derived from precursor sequences. Curr. Med. Chem.,11:2651–2665.

4.     Edison AS, Espinoza E, Zachariah C (1999). Conformational Ensembles: The Role of Neuropeptide Structures in Receptor Binding. The Journal of Neuroscience., 19(15):6318-6326.

5.     Payza K, Greenberg MJ, Price DA (1989). Further characterization of Helix FMRFamide receptors: kinetics, tissue distribution, and interactions with the endogenous heptapeptides. Peptides, 10:657-661.

6.     Allen J, Novotný J, Martin J, Heinrich G (1987). Molecular structure of mammalian neuropeptide Y: Analysis by molecular cloning and computer-aided comparison with crystal structure of avian homologue. PNAS., 84:2532-2536.

7.     Guya J, Lia S,  Pelletier G (1988). Studies on the physiological role and mechanism of action of neuropeptide Y in the regulation of luteinizing hormone secretion in the rat. Regulatory Peptides., 23(2):209-216.