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BQ-123是一种有效的内皮素拮抗剂，对ET-a受体亚型具有高选择性。

BQ-123 is a potent endothelin antagonist with high selectivity for the ET-A receptor subtype.

BQ-123是一种阻断内皮素a受体的环肽。它已被证明是治疗与骨关节炎，类风湿性关节炎和其他炎症相关的疼痛和炎症的有效方法。

BQ-123 is a cyclic peptide that blocks the endothelin-A receptor. It has been shown to be an effective treatment for pain and inflammation associated with osteoarthritis, rheumatoid arthritis, and other inflammatory conditions.

BQ-123与内皮素A受体结合，内皮素A受体位于全身许多组织的细胞表面。当结合时，它通过减少电压门控钙通道来抑制细胞内钙浓度，并阻止神经递质的释放。由于其带电荷的侧链，BQ-123还对氢键具有稳定作用。这种特性可能解释了它与其他蛋白质形成稳定复合物的能力，从而抑制了它们的功能。\已显示nBQ-123在环AMP反应元件结合蛋白（CREB）上具有活性结合位点，可抑制CREB活性，从而减少蛋白质合成。它还阻断环状GMP（cGMP）依赖性蛋白kin

BQ-123 binds to the endothelin-A receptor, which is located on the surface of cells in many tissues throughout the body. When bound, it inhibits intracellular calcium concentrations by reducing voltage-gated calcium channels and prevents the release of neurotransmitters. BQ-123 also has a stabilizing effect on hydrogen bonds due to its charged side chains. This property may account for its ability to form stable complexes with other proteins, inhibiting their function.\nBQ-123 has been shown to have an active binding site on cyclic AMP response element binding protein (CREB) that inhibits CREB activity, thereby reducing protein synthesis. It also blocks cyclic GMP (cGMP)-dependent protein kin

BQ-123 是合成环肽，用于研究内皮素 - 受体系统中的结构决定因素。其明确环拓扑支持结合、折叠与对接分析。该序列有助于定位多肽 - 蛋白质识别的最小基序。应用包括配体建模与结构生物化学。

BQ-123 is a synthetic cyclic peptide used to investigate structural determinants within endothelin-receptor systems. Its defined loop topology supports binding, folding, and docking analyses. The sequence aids in mapping minimal motifs responsible for peptide-protein recognition. Applications include ligand modeling and structural biochemistry.

BQ-123 是 A 型内皮素受体多肽拮抗剂，半数抑制浓度 7.3 纳摩尔，对 A 型受体选择性远高于 B 型受体。它可抑制内皮素 1 诱导的人肺动脉平滑肌细胞增殖，逆转内皮素 1 造成的大鼠平均动脉压升高。静脉注射 3 毫克 / 千克剂量，能够延长戊四氮致痫模型大鼠癫痫发作潜伏期，减少重度癫痫发作个体数量。

BQ-123 is a peptide endothelin type A (ET ) receptor antagonist (IC = 7.3 nM). It is selective for ET over ET receptors (K s = 0.025 and 31 µM, respectively). BQ-123 inhibits growth of human pulmonary artery smooth muscle cells induced by endothelin-1 (ET-1; Item No. 24127 ). It reverses ET-1-induced increases in mean arterial pressure (MAP) in rats. BQ-123 (3 mg/kg, i.v.) also delays seizure onset and reduces the number of rats with major seizures in a model of epilepsy induced by pentylenetetrazole (PTZ; Item No. 18682 ).

BQ-123 BQ-123是一种高效、选择性内皮素 A (ETA) 受体拮抗剂，IC50 值为 7.3 nM，Ki 值为 25 nM。BQ-123 抑制内皮素-1 介导的人肺动脉平滑肌细胞增殖，降低高血压大鼠血压。 体内研究： 持续输注 BQ-123（每分钟 0.16-164 nmol/kg，静脉注射，持续 6 小时）可在自发性高血压大鼠 (SHR) 中产生剂量依赖性平均动脉压降低，剂量为 16 nmol 时获得最大降低/千克每分钟。 BQ-123（3 mg/kg；静脉注射；在戊四唑 (PTZ) 前 15 分钟给予）在 PTZ（50 mg/kg；腹腔注射）+BQ-123 组中很大程度上阻止癫痫发作的形成和扩散。
 

Definition

A peptidergic activity produced in endothelial cells that caused coronary vasoconstriction was described in 1985, and a family of peptides, named the endothelins, was subsequently isolated and identified. The three members of the family — endothelin-1 (ET-1), endothelin-2 (ET-2), and endothelin-3 (ET-3 )— are produced in a variety of tissues, where they act as modulators of vasomotor tone, cell proliferation, and hormone production 1.

Related Peptides

The 21-amino acid peptide ET-1 is the predominant isoform of the endothelin peptide family, which includes ET-2, ET-3, and ET-4. It exerts various biological effects, including vasoconstriction and the stimulation of cell proliferation in tissues both within and outside of the cardiovascular system. ET-1 is synthesized by endothelin-converting enzymes (ECE), chymases, and non-ECE metalloproteases; it is regulated in an autocrine fashion in vascular and nonvascular cells 2.

Discovery

Endothelin, one of the most potent vasoconstrictors, was first discovered by Yanagisawa and co-workers in 1981. It was first isolated, characterized, and cloned in porcine aortic endothelial cells 3.

Structural Characteristics

First of the three isoforms, the ET-1, is a 21-amino acid peptide; it has a molecular weight of 2,492, free carboxyl and amino termini and has two intramolecular disulfide bonds. It is present in many mammalian species, including humans. Other two human endothelin isopeptides, ET-2 and ET-3 are encoded by separate genes. They contain two intramolecular disulfide bonds. They also contain a cluster of polar charged side chains in the hairpin loop and a hydrophobic COOH terminus, containing the aromatic indole side chain at trp21 3.

Mode of Action

Two endothelin receptors have been characterised in the mammals. They are classified according to the relative binding affinities of the 3-endothelin isopeptides to the receptors. The order of affinity of endothelins for 1st receptor type designated ETA is ET-1 > ET-2 > ET- 3. The second receptor subtype designated ETB shows equipotent affinity for all 3 endothelins 3.

Functions

Endothelins appear to act mainly as local paracrine/autocrine peptides, but circulating levels of endothelins also have great biological significance especially in pathological states of increased serum concentration.

Pathophysiology of Endothelins:

1. Renal haemodynamics: In various studies in dogs and rats it has been seen that endothelin peptides have both contractile and promitogenic actions in renal mesangial cells.
2. Renal disease: In various studies it has been shown that ET-1 plays a role in the pathogenesis of acute renal failure after renal ischaemia, i.e., plasma levels of ET-1 are increased in patients with acute renal failure.
3. Hypertension: ET-1 causes potent vasoconstriction and prolonged elevation of blood pressure in experimental models. But the relationship between the plasma levels of ET-1 and severity of hypertension is inconsistent in humans.
4. Heart failure: Plasma endothelin levels are increased in animal models of CHF (Chronic Heart Failure) and in patients with CHF. In patients, increased plasma endothelin levels correlate closely with the degree of haemodynamic and functional impairment, with higher levels predicting a greater likelihood of death or need for cardiac transplantation.
5. Ischaemic heart disease: In human studies, plasma endothelin levels are increased in unstable angina and acute myocardial infarction.
6. Variant angina: Patients with Prinzmetal’s angina are known to have endothelial dysfunction affecting the L-arginine nitric oxide system, and as a potent vasoconstrictor of coronary arteries, endothelin-1 has been implicated in the pathophysiology of this condition.
7. Primary pulmonary hypertension: In primary pulmonary hypertension there is proliferation of pulmonary arterial smooth muscle and endothelial injury. It has been observed that depending on the state of vasomotor tone, endothelin isopeptides can cause either pulmonary vasodilatation or vasoconstriction.
8. Raynaud’s disease: Raynaud’s disease is seen commonly in cold climates and is associated with vasospastic conditions like migraine and Prinzmetal’s angina. There has been exaggerated increase in endothelin levels in venous blood draining from the cold challenged arm, in cases with Raynaud’s disease as compared with responses in healthy volunteers.
9. Subarachnoid haemorrhage (SAH): Endothelin-1 has a causative role in mediating sub-arachnoid hemorrhage induced vasospasm. Plasma and CSF endothelin levels are significantly increased in patients after SAH and plasma levels of endothelins are highest in those who develop vasospasm.
10. Migraine: In the recent studies it has been found that levels of endothelins are increased during migraine headaches 3.

References

1. Levin ER (1995). Endothelins. NEJM., 333:356-363.
2.  Lüscher TF, Barton M (2000). Endothelins and Endothelin Receptor Antagonists Circulation., 102:2434:2440.
3. Jain SK, Yadava RK, Raikar R (2002). Role of Endothelins in Health and Disease. JIACM,  3(1):59-64.

【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。