CN114099513B - 唑类化合物在制备醛酮还原酶akr7增效剂中的应用 - Google Patents
唑类化合物在制备醛酮还原酶akr7增效剂中的应用 Download PDFInfo
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- CN114099513B CN114099513B CN202111234872.0A CN202111234872A CN114099513B CN 114099513 B CN114099513 B CN 114099513B CN 202111234872 A CN202111234872 A CN 202111234872A CN 114099513 B CN114099513 B CN 114099513B
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Abstract
本发明公开了唑类化合物在制备醛酮还原酶AKR7增效剂中的应用。本发明比较了人AKR7A2在五种唑类化合物存在或不存在时，代谢底物琥珀酸半醛(SSA)的酶活情况，所述AKR7A2为醛酮还原酶7家族A2成员。表明泊沙康唑、酮康唑、咪康唑、伏立康唑和伊曲康唑具有显著增强AKR7A2酶活的作用，同时泊沙康唑对AKR7A3和AKR7A5也有显著的增强酶活的作用。其中泊沙康唑、伏立康唑和伊曲康唑是口服或注射用药，可在体内发挥增强AKR7醛酮还原酶7家族酶活的作用。
Description
技术领域
本发明涉及化合物新功能技术领域。具体的，涉及唑类化合物在制备醛酮还原酶AKR7增效剂中的应用。
背景技术
唑类化合物属于杂环化合物，在20世纪60年代末开发上市，常用于真菌感染的治疗，并在人体内具有广泛的抗真菌谱。唑类化合物可分为咪唑类以及三唑类衍生物，其作用机制是通过竞争性抑制真菌羊毛甾醇14α-脱甲基酶(一种细胞色素P450酶)，干扰了细胞膜麦角甾醇的合成，破坏了真菌质膜的完整性，从而起到抑菌作用。唑类化合物，对侵入性真菌感染的治疗产生了重大影响。人们通常使用咪唑类(酮康唑和咪康唑)用于治疗浅表霉菌病。相应地，为了满足更广泛的应用，科研人员开发了三唑类化合物(伊曲康唑，伏立康唑和泊沙康唑)。
咪康唑是第一种投放市场的咪唑类化合物，其具有广谱、高效和不良反应小的优点，被广泛应用于临床治疗，主要用于皮肤癣菌和念珠菌引起的皮肤和粘膜感染。其常见的剂型有软膏、栓剂、阴道用软胶囊等。酮康唑的活性谱与咪康唑相似，但由于其具有严重的肝毒性，其口服使用已被禁止。并且酮康唑对细胞色素P450 3A4酶(CYP3A4)存在抑制作用，可能会导致许多临床上的相关药物相互作用，因此对酮康唑的使用也变得更为严谨。尽管有很多局限性，但酮康唑依然成为了慢性粘膜皮肤念珠菌病的首选药物，并在近十年来，替代了多烯抗真菌两性霉素B脱氧胆酸盐，用于许多非危及生命的系统性酵母菌感染。
第一代三唑类药物伊曲康唑对念珠菌病表现出非常好的活性，但对治疗侵袭性丝状真菌病的效果不如两性霉素B。而第二代三唑类抗真菌药伏立康唑和泊沙康唑在保留第一代三唑类药物效果的基础上，增强了抵抗丝状真菌感染的活性，为广谱抗真菌药。伊曲康唑对许多临床常见的念珠菌、新型隐球菌和粗球孢子菌都有很好的活性，且对克柔念珠菌、烟曲霉菌、镰刀菌属及丝孢菌属具有一定活性。除此之外，伏立康唑还增加了对光滑念珠菌、克柔念珠菌、烟曲霉菌和镰刀菌属的抗菌活性，但对毛霉菌属仍几乎无效。随后研发出的泊沙康唑则增加了对毛霉菌属的活性，抗菌谱为最广泛。目前为止，唑类药物主要用于真菌感染的治疗，其在酶的活性调节方面的应用尚未见报道。
酶的增效剂和抑制剂在酶的活性调节中发挥重要作用，研究酶的激活和抑制作用具有潜在的应用价值。醛酮还原酶(aldo-keto reductases，AKRs)是NAD(P)(H)依赖性氧化还原酶，在体内分布广泛。人AKR7A2是醛酮还原酶7家族成员之一，其主要作用是将醛酮类化合物转化为相应的醇类物质，并是人中枢神经系统中主要的琥珀酸半醛还原酶。γ-羟基丁酸(GHB)是哺乳动物脑和其他器官的内源性化合物，在中枢神经系统中，它表现出对多巴胺合成和释放的神经调节作用。γ-氨基丁酸(GABA)被单胺氧化酶降解产生琥珀酸半醛(SSA)，SSA的一部分会通过琥珀酸半醛还原酶AKR7A2代谢成GHB。AKR7A2还可将黄曲霉毒素二醛转变为无毒的黄曲霉毒素二醇，在黄曲霉毒素的代谢过程中起到解毒的作用。同时，AKR7A2还具有代谢细胞内氧化应激所产生的活性醛(4-HNE)，保护细胞免受氧化应激损伤的能力。有研究发现，AKR7A2的表达量在阿尔茨海默症患者大脑的特定区域里是升高的。AKR7A2还存在于肝脏和肾脏等其他组织中。同时还发现，AKR7A2具有代谢细胞内氧化应激所产生的活性醛(4-HNE)，保护细胞免受氧化应激损伤的能力。
专利201310549552.3公开了三唑类化合物在制备乙醛脱氢酶2激活剂中的应用，专利200580031257.2公开了咪唑衍生物可作为大电导钙激活K通道开启剂。但目前并没有报导泊沙康唑、酮康唑、咪康唑、伏立康唑和伊曲康唑在激活AKR7的用途。
发明内容
本发明的目的是克服现有技术的上述不足，提供一种唑类化合物在作为抗真菌药物之外的新用途，所述唑类化合物能够增强AKR7酶活，能够极大的促进和提高酶的代谢活性。
本发明的第一个目的是提供一种三唑类和/或咪唑类化合物作为醛酮还原酶AKR7的催化效率增效剂的应用
本发明的第二个目的是提供一种三唑类和/或咪唑类化合物在制备醛酮还原酶AKR7的催化效率增效剂中的应用。
本发明的第三个目的是提供一种提高醛酮还原酶催化效率的组合物。
本发明的第四个目的是提供一种提高AKR7醛酮还原酶催化效率的方法。
为了实现上述目的，本发明是通过以下方案予以实现的：
三唑类和/或咪唑类化合物作为醛酮还原酶AKR7的催化效率增效剂的应用，所述AKR7为醛酮还原酶7家族。
三唑类和/或咪唑类化合物在制备醛酮还原酶AKR7的催化效率增效剂中的应用，所述AKR7为醛酮还原酶7家族。
优选地，三唑类和/或咪唑类化合物在制备醛酮还原酶AKR7在黄曲霉毒素的代谢过程解毒和/或保护细胞免受氧化应激损伤增效剂中的应用，所述AKR7为醛酮还原酶7家族。
优选地，所述三唑类化合物为泊沙康唑、伏立康唑和/或伊曲康唑中的一种或几种，所述咪唑类化合物为酮康唑和/或咪康唑。
优选地，所述AKR7为AKR7A2、AKR7A3和/或AKR7A5中的一种或几种，所述AKR7A2为醛酮还原酶7家族A2成员，所述AKR7A3为醛酮还原酶7家族A3成员，所述AKR7A5为醛酮还原酶7家族A5成员。
一种提高醛酮还原酶催化效率的组合物，含有AKR7，以及三唑类和/或咪唑类化合物。
优选地，所述三唑类化合物为泊沙康唑、伏立康唑和/或伊曲康唑中的一种或几种，所述咪唑类化合物为酮康唑和/或咪康唑。
优选地，所述AKR7为AKR7A2、AKR7A3和/或AKR7A5中的一种或几种，所述AKR7A2为醛酮还原酶7家族A2成员，所述AKR7A3为醛酮还原酶7家族A3成员，所述AKR7A5为醛酮还原酶7家族A5成员。
一种提高AKR7醛酮还原酶催化效率的方法，所述AKR7为醛酮还原酶7家族，将AKR7与三唑类和/或咪唑类化合物联用。
优选地，所述三唑类化合物为泊沙康唑、伏立康唑和/或伊曲康唑中的一种或几种，所述咪唑类化合物为酮康唑和/或咪康唑。
优选地，所述AKR7为AKR7A2、AKR7A3和/或AKR7A5中的一种或几种，所述AKR7A2为醛酮还原酶7家族A2成员，所述AKR7A3为醛酮还原酶7家族A3成员，所述AKR7A5为醛酮还原酶7家族A5成员。
一种非治疗目的提高AKR7醛酮还原酶催化效率的方法，所述AKR7为醛酮还原酶7家族，将AKR7与三唑类和/或咪唑类化合物联用。
优选地，所述三唑类化合物为泊沙康唑、伏立康唑和/或伊曲康唑中的一种或几种，所述咪唑类化合物为酮康唑和/或咪康唑。
优选地，所述AKR7为AKR7A2、AKR7A3和/或AKR7A5中的一种或几种，所述AKR7A2为醛酮还原酶7家族A2成员，所述AKR7A3为醛酮还原酶7家族A3成员，所述AKR7A5为醛酮还原酶7家族A5成员。
本发明比较了人AKR7A2在五种唑类化合物存在或不存在时，代谢底物琥珀酸半醛(SSA)的酶活情况，所述AKR7A2为醛酮还原酶7家族A2成员。表明泊沙康唑，酮康唑，咪康唑，伏立康唑和伊曲康唑具有显著增强AKR7A2酶活的作用。同时泊沙康唑对AKR7A3和AKR7A5也有显著的增强酶活的作用。其中泊沙康唑，伏立康唑和伊曲康唑是口服或注射用药，可在体内发挥增强AKR7醛酮还原酶7家族酶活的作用。
与现有技术相比，本发明具有以下有益效果：
唑类化合物作为治疗真菌感染的化合物在临床上有广泛的使用，本发明发现唑类化合物的新用途，其可作为人AKR7醛酮还原酶7家族增效剂，提高AKR7醛酮还原酶7家族的催化效率，具有增强其酶活的作用，增强其代谢某些毒素的能力，该发明表明口服或注射用的唑类化合物可用于提高人AKR7的酶活，从而增强其代谢内源和外源底物的效率，在临床上具有良好的应用价值。
附图说明
图1为重组人AKR7A2蛋白胶检测的结果，所述AKR7A2为醛酮还原酶7家族A2成员。其中，M为标准蛋白；1为诱导前；2为诱导后；3为膜组分溶解后离心沉淀；4为膜组分溶解后离心上清；5为上样穿透的蛋白；6～12为均为洗脱的蛋白样品。
图2为不同浓度泊沙康唑、酮康唑、咪康唑、伊曲康唑和伏立康唑存在时，AKR7A2催化SSA的动力学曲线，其中，A为泊沙康唑、B为酮康唑、C为咪康唑、D为伊曲康唑、E为伏立康唑。
图3为不同浓度泊沙康唑对AKR7A3催化2-CBA的影响。
图4为不同浓度泊沙康唑对AKR7A5催化2-CBA的影响。
图5为泊沙康唑、酮康唑、咪康唑、伊曲康唑和伏立康唑与AKR7A2的对接模型。
具体实施方式
下面结合说明书附图及具体实施例对本发明作出进一步地详细阐述，所述实施例只用于解释本发明，并非用于限定本发明的范围。下述实施例中所使用的试验方法如无特殊说明，均为常规方法；所使用的材料、试剂等，如无特殊说明，为可从商业途径得到的试剂和材料。
实施例1重组AKR7A2蛋白的表达与纯化
本研究首先根据NCBI公布的基因序列设计特异引物，从人293T细胞的cDNA中克隆了AKR7A2基因。利用pET-28a载体，在大肠杆菌BL21 pLysS中表达了重组蛋白，运用Ni2+亲和纯化得到纯度达95％以上的目的蛋白。具体实施方法如下：
(1)根据NCBI上人AKR7A2的序列，设计特异的扩增引物，所述AKR7A2的序列如SEQID NO：1所示。从人293T细胞的cDNA中扩增得到目的片段，再将其构建到pET28a表达载体上。反应条件参考KOD Plus酶体系。
(2)取0.5μL的构建好的质粒，加入50μL的E.coli BL21的感受态，冰上放置30min；感受态在42℃的水浴90s热激，涂布于卡那霉素浓度为50mg/L的平板，37℃培养；约10h后，挑取单克隆至5mL含卡那霉素抗性LB液体培养基中，37℃，200rpm，6～7h；1：100(V/V)接种于500mL LB培养基(卡那霉素终浓度50mg/L)，37℃，200rpm；摇菌至OD600值达到0.6；加入IPTG至终浓度1mM开始诱导，18h，16℃，150rpm；冰浴30min后，在3500g，20min，4℃条件下离心，弃掉上清；-80℃保存。
(3)-80℃过夜后，冰上化冻，20％功率超声破碎，工作10s，间隔10s，40次循环；破碎后的菌液20000g，4℃离心20min，收上清。过0.45μM膜，得到样品准备亲和纯化。
亲和纯化：打开FPLC主机和软件，设计纯化程序；用超纯水冲洗需要使用的泵，保证管路没有空气，并在流动的状态下接上5mL镍柱，冲洗柱子中的20％的乙醇；用缓冲液A平衡纯化用的镍柱，运行5个柱体积；根据待纯化的蛋白样品液体体积，设定相应的上样程序，控制流速1mL/min，然后根据设置好的程序纯化，收集蛋白，每管5mL；运行完后，先用超纯水冲洗2个柱体积，然后用2mM咪唑冲洗20mL；运行完后，先用超纯水冲洗2个柱体积，然后用2mM NaCl冲洗20mL；清洗完毕后，用超纯水冲洗2个柱体积，将A、B泵保存在20％乙醇中；
结果如图1所示，重组人AKR7A2蛋白的理论分子量为39.8kDa，纯化得到的蛋白大小与其理论分子量相同，纯度达到95％以上，浓度为0.3mg/mL满足后续实验要求。
根据蛋白胶检测的结果，把收集的蛋白加入透析袋中，放入透析液中(100mM磷酸钠缓冲液pH 7.4，500mM氯化钠，10％甘油，pH 7.4)，4℃，慢速搅拌12h，然后分装，冻存于-80℃。
实施例2唑类化合物对AKR7A2酶活的影响
琥珀酸半醛(SSA)作为人AKR7A2的模式底物，可被其还原为γ-羟基丁酸(GHB)。为了了解唑类药物对重组AKR7A2酶活的影响，我们进行了相应的酶促动力学实验。
在25℃，100mM磷酸钠缓冲液(pH 7.0)的条件下，分别加入不同浓度的唑类药物，以每分钟消耗NADPH的摩尔浓度的反应速度对底物SSA的浓度作图，使用GrapHPad Prism软件，用米氏方程对实验数据进行非线性拟合，具体实施方法如下：
(1)重组AKR7A2催化SSA的稳态动力学。通过监测NADPH在340nm的氧化速率，测定重组蛋白对模式底物琥珀酸半醛(SSA)的稳态动力学参数。使用岛津UV-2550分光光度计，1cm光程比色皿，标准反应体系按顺序加入100mM磷酸钾缓冲液(pH 7.0)、0.2mM NADPH、0.4μM实施例1获得的纯化的重组AKR7A2和不同浓度(0、3.68、8.27、13.78、22.97、44.10、66.15和95.55μM)的底物，总体积0.8mL。底物加入前对吸收值进行调零，加入SSA后启动反应，在25℃记录波长340nm处吸收值的变化。
(2)唑类化合物存在时重组AKR7A2催化SSA的稳态动力学。在上述反应体系中加入不同浓度的泊沙康唑(PSZ 5μM、20μM和50μM)、伊曲康唑(ITZ 20μM和50μM)、伏立康唑(VCZ5μM、20μM和50μM)、酮康唑(KTZ 20μM、50μM和100μM)以及咪康唑(MCZ 5μM、20μM和50μM)，底物SSA加入前对吸收值进行调零，加入底物后起始反应，在25℃记录波长340nm处吸收值的变化。
如图2(A～E)显示，在不同浓度的唑类化合物——泊沙康唑、酮康唑、咪康唑、伊曲康唑和伏立康唑存在时，AKR7A2催化SSA的动力学曲线符合米氏方程(R2>0.99)。
拟合得到的稳态动力学数据显示，在泊沙康唑、酮康唑、咪康唑、伊曲康唑和伏立康唑存在时，AKR7A2对底物的催化效率(kcat/Km)均显著增强，并且这种增强作用与化合物浓度呈正相关(表1)。因此，泊沙康唑、酮康唑、咪康唑、伊曲康唑和伏立康唑是AKR7A2的增效剂。其中，泊沙康唑对AKR7A2的激活作用最显著，在50μM泊沙康唑存在下，AKR7A2对SSA的催化效率(kcat/Km)相比无唑类化合物存在时提高超过80％(表1)。
表1泊沙康唑、酮康唑、咪康唑、伊曲康唑和伏立康唑存在时，AKR7A2对底物SSA的催化情况
当AKR7A2浓度为0.8μM时，泊沙康唑对AKR7A2催化底物SSA的影响见表2。
可以看出泊沙康唑对酶的催化效率仍具有增强作用，相比无泊沙康唑存在时提高了48％。
表2泊沙康唑对0.8μM AKR7A2催化活性的影响
实施例3泊沙康唑对AKR7家族其它成员酶活的影响
采用实施例1的方法获得的纯化AKR7A3和AKR7A5，其中AKR7A3的氨基酸序列如SEQID NO：2所示，AKR7A5的氨基酸序列如SEQ ID NO：3所示。当以2-羧基苯甲醛(2-CBA)作为AKR7家族酶的底物时，2-CBA浓度梯度为：0、1.25、3.75、8.75、12.5、25、43.75、62.5和93.75μM。采用实施例2相同的实验方法，记录泊沙康唑浓度分别为0、5和20μM时，AKR7A3和AKR7A5对底物2-CBA催化活性的影响。
从图3和图4可以看出，在不同浓度的泊沙康唑存在时，AKR7A3和AKR7A5催化2-CBA的动力学曲线符合米氏方程(R2>0.99)。
结果显示泊沙康唑对AKR7家族其它成员(AKR7A3和AKR7A5)也有增强酶活的作用(表3)。
表3泊沙康唑存在时，AKR7A3和AKR7A5对底物2-CBA催化活性的影响
实施例4唑类药物在AKR7A2分子上的结合模型
利用分子对接软件AutoDock 4.2对五种唑类药物在酶分子上的结合位点进行了模拟。
预测得到的药物在酶分子上的结合模型见图5。图中A-E分别为泊沙康唑(青色)，酮康唑(棕色)，咪康唑(蓝色)，伊曲康唑(紫色)和伏立康唑(绿色)与AKR7A2的对接模型。橙色的分子是NADPH(AKR7A2催化反应所需的还原剂)，黄色的分子为底物。该模型表明泊沙康唑可结合在AKR7A2底物口袋腔外侧，有助于稳定底物在活性中心的结合，提高酶对底物的催化效率。
最后所应当说明的是，以上实施例仅用以说明本发明的技术方案而非对本发明保护范围的限制，对于本领域的普通技术人员来说，在上述说明及思路的基础上还可以做出其它不同形式的变化或变动，这里无需也无法对所有的实施方式予以穷举。凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明权利要求的保护范围之内。
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Claims (2)
1.三唑类和/或咪唑类化合物在制备醛酮还原酶AKR7的催化效率增效剂中的应用，其特征在于，所述AKR7为醛酮还原酶7家族，
所述三唑类化合物为泊沙康唑、伏立康唑和/或伊曲康唑中的一种或几种，所述咪唑类化合物为酮康唑和/或咪康唑，
所述AKR7为AKR7A2、AKR7A3和/或AKR7A5中的一种或几种，所述AKR7A2为醛酮还原酶7家族A2成员，所述AKR7A3为醛酮还原酶7家族A3成员，所述AKR7A5为醛酮还原酶7家族A5成员。
2.一种提高醛酮还原酶催化效率的组合物，其特征在于，含有AKR7，以及三唑类和/或咪唑类化合物，
所述三唑类化合物为泊沙康唑、伏立康唑和/或伊曲康唑中的一种或几种，所述咪唑类化合物为酮康唑和/或咪康唑，
所述AKR7为AKR7A2、AKR7A3和/或AKR7A5中的一种或几种，所述AKR7A2为醛酮还原酶7家族A2成员，所述AKR7A3为醛酮还原酶7家族A3成员，所述AKR7A5为醛酮还原酶7家族A5成员。
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