摘要
CFTR(cystic fibrosis transmembrane conductance regulator)即囊性纤维化跨膜电导调节因子,是一种受cAMP调节的氯离子通道,在呼吸道、胃肠道、胰腺、睾丸及汗腺等处的上皮细胞广泛表达,主要参与电解质及液体的转运。该通道活动的异常与多种疾病的病理发生相关,CFTR氯离子通道功能丧失或活性降低可导致囊性纤维化、慢性胰腺炎、男性不孕、便秘和干眼病等,而功能的过度激活则与分泌性腹泻、多囊肾病等疾病的发生关系密切,因此CFTR氯离子通道高效、特异性调节剂的发现对于研究这些疾病的病理机制和治疗有重要价值。
本文的目的之一是从中药单体化合物库中筛选wt-CFTR氯离子通道的激活剂并对其分子药理学特征进行系统研究。利用碘离子高度敏感的wt-CFTR氯离子通道荧光测定细胞模型,对386种中药单体化合物进行了筛选,得到了14种能够明显促进碘离子转运的单体化合物,它们在结构上分别属于香豆素类、蒽醌类、生物碱类、黄酮类及萜类等5个天然化合物家族。活性最高的是香豆素类化合物,其中的蛇床子素对wt-CFTR的EC50约为100nM/L,是迄今为止发现的对wt-hCFTR亲和力最高的天然激活剂。动物体外研究表明蛇床子素能够刺激小鼠咽喉部粘膜下腺液体的分泌以及大鼠肠粘膜上皮的氯离子短路电流,这些结果揭示了香豆素类化合物的新药理作用,并且为将它们开发为与CFTR氯离子通道功能障碍相关疾病治疗的药物提供了理论依据。另外,蒽醌类化合物也是wt-CFTR氯离子通道的有效激活剂,该类化合物是大黄类导泻药的活性成份,被广泛用于便秘的治疗,但其发挥导泻作用的确切靶点尚不清楚。本研究通过大鼠结肠短路电流分析及小鼠结肠液体分泌研究,推测大黄等中草药发挥泻下作用的主要机制之一可能是大黄酸等蒽醌类化合物对CFTR氯离子通道的直接激活。
本文的另一目的是筛选?F508-CFTR氯离子通道的天然激活剂(Potentiator)及蛋白质质膜转运障碍纠正剂(Corrector)并对其分子药理学特征进行系统研究。CFTR基因突变致使其离子通道功能丧失或活性降低,从而导致囊性纤维化,该疾病影响多种器官的生理功能。其中最常见的是?F508-CFTR这种缺失突变,至少存在于90%的囊性纤维化患者的一个等位基因上,第508位苯丙氨酸的缺失在两个方面对CFTR的功能产生影响并最终造成CFTR的Cl-转运功能丧失,一方面蛋白质无法正常到达质膜,另一方面即使是能够到达质膜,通道的氯离子转运活性也明显降低。尽管目前国际上已经发现了一些能够纠正?F508-CFTR功能缺陷的小分子化合物,但在天然产物的研究方面进展甚微。本研究利用碘离子高度敏感的?F508-CFTR氯离子通道荧光测定细胞模型,从386种中药单体化合物中筛选获得了14种能够显著促进?F508-CFTR通道离子转运活性的化合物,分别属于香豆素类、蒽醌类、生物碱类、黄酮类及萜类等5个天然化合物家族。其中活性最强的是欧前胡素,EC50约为15μM/L,它们对?F508-CFTR的激活作用依赖于cAMP,且具有快速和可逆的特点,对细胞内cAMP的浓度没有影响,且与IBXM及forskolin的混合激活剂有相加作用,表明它们可能是通过与?F508-CFTR直接结合而起到激活作用的。通过构-效关系分析,推测该类化合物母核结构的第六、七、八位取代基性质共同决定了其激活作用的强弱,疏水性越强活性越高。通过扩大筛选规模或以欧前胡素为先导化合物进行结构优化,应该能够得到亲和力更高的激活剂。同时,我们也对386种中药单体化合物的?F508-CFTR质膜运送障碍纠正剂的活性进行了筛选,发现仅有白杨素能够在一定程度上促进?F508-CFTR向质膜的运送,但是与以往发现的组合小分子纠正剂相比活性较弱。通过结构修饰增强白杨素的活性可能使其在囊性纤维化及相关疾病的机理研究和药物治疗方面发挥作用。
本研究通过对天然中药单体化合物进行筛选,得到了多种野生型和突变CFTR氯离子通道激活剂并对它们的激活作用进行了系统的药理学研究,这些天然化合物对于囊性纤维化及其它CFTR相关疾病的机理研究和治疗具有重要价值,同时也为将天然产物资源用于现代药物发现提供了依据。
CFTR( cystic fibrosis transmembrane conductance regulator) is a chloride channel regulated by cAMP. It is expressed by epithelium lined airway, gastrointestinal tract, pancreatic, sweat gland, testis,et al, and involved in transport of electrolyte and fluid. The abnormal activity of CFTR chloride channel is related to pathogenesis of several diseases. Disfunction will result in cystic fibrosis, chronic pancreatitis, male sterility,constipation, et al. Overactivity has important role in the generation of diarrhea, ADPKD. So the modulators of this ion channel is valuable to the theraphy of these diseases.
One purpose of this paper is to identify natural compounds from Chinese herbs that can stimulate the activity of wt-hCFTR chloride channel and to characterize their molecular pharmacological activity systematically. We use a FRT cell line stably coexpressing wt-hCFTR and a ultra-high halide sensitive (YFP-H148Q) EYFP and find 14 compounds which can stimulate iodide transport mediated by wt-CFTR from 386 natural compounds. They belong to coumarin, alkaloid, flavonoid and terpenoid and the most potential compounds are coumarins. Among them, EC50 value of osthole is only 100nM/L and is the most high affinity natural activator for wt-hCFTR at present. Osthole can stimulate the fluid secretion of submucosal gland at mouse pars laryngea pharyngis and elevate short circuit current across rat colonic mucosal epithelium. These results show the new pharmacological action of osthole and evaluate its potential therapeutic value for chronic pancreatitis and male sterility. We identified several anthraquinone compounds as wt-CFTR activators, as as Rhein, Aloe-emodin. They are also the effective constituents of cathartic herbs, but it is not clear for its definite target as catharsis. Our detailed study prove that the direct activation of Rhein to wt-CFTR is one mechanism of rhubarb as eliminate.
Another purpose of this paper is to identify natural compounds from Chinese herbs that can correct defectiveΔF508-CFTR channel gating and membrane trafficking and also to evaluate their potential as therapeutic agents. CFTR mutations result in cystic fibrosis disease which influences functions of many organs. ?F508-CFTR is the most common mutation and is present in at least one allele in 90% of CF patients. Deletion of phenylalanine at 508 position causes two distinct defects in CFTR: (i) defect trafficking to plasma membrane and (ii) impaired intrinsic Cl- conductance (reduced open channel probability) after reaching cell surface.At present, several compounds correcting the function of ?F508-CFTR have been found,but most of them belong to synthetic compounds and are difficult to be developed as medicine. We use a FRT cell line stably coexpressingΔF508-CFTR and a ultra-high halide sensitive (YFP-H148Q/I152L) EYFP and find 14 compounds which can facility iodide transport mediated byΔF508-CFTR from 386 natural compounds. They belong to coumarin, alkaloid, flavonoid and terpenoid and the most potential compounds are coumarins. Pharmacological properties of these compounds were characterized systematically. Imperatorin is the most potential compound and EC50 is 15μM/L. Their action is dependent on forskolin, action quickly and reversibly. We suppose these potentiators activate ?F508-CFTR by directly binding, because they cannot elevate cAMP concentration and have additive effection with mixture of forskolin and IBMX. After structure and activity relationship analysis, we find the hydrophobicity of substitutions at six, seven, eight postion together decides the strong or weak activity. Additionally, we screen correctors of ?F508-CFTR and find Chrysin at higher concentration can promote ?F508-CFTR trafficking to plasma membrane at some extend. By larger screening or optimized the structure of Imperatorin and Chrysin, better activity and higher affinity potentiators and correctors should be found and as candidate for CFTR related disease therapy.
We identify several CFTR potentiators from natural Chinese medicine compounds and identify their pharmacological activity. These compounds are very valuable to treat cystic fibrosis and other CFTR related diseases. Our study also affords a theory basis for the utilization of traditional Chinese medicine in modern drug discovery.
引文
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