CN118141811A - Yap/taz抑制剂-2在制备预防和/或治疗由病原微生物感染引起的角膜疾病药物中的应用 - Google Patents
Yap/taz抑制剂-2在制备预防和/或治疗由病原微生物感染引起的角膜疾病药物中的应用 Download PDFInfo
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Abstract
本发明涉及YAP/TAZ抑制剂‑2和/或其衍生物在制备预防和/或治疗由病原微生物感染引起的角膜疾病药物中的应用，属于生物医药技术领域。本发明首次发现在细胞实验水平和动物实验水平上发现YAP/TAZ抑制剂‑2能够有效抵抗由DI引起的角膜损伤。通过细胞实验发现YAP/TAZ抑制剂‑2能够激活角膜上皮细胞特性基因的表达，促进角膜上皮细胞分化；通过动物实验发现YAP/TAZ抑制剂‑2能够有效缓解角膜上皮细胞病变，维持角膜的透明性和完整性，使角膜的特性和生理功能恢复正常。
Description
技术领域
本发明涉及生物医药技术领域，尤其涉及YAP/TAZ抑制剂-2在制备预防和/或治疗由病原微生物感染引起的角膜疾病药物中的应用。
背景技术
感染性角膜疾病是指角膜受病毒、真菌或细胞菌等病原体感染而引起的炎症和组织病变。角膜浅层有丰富的三叉神经末梢，故该病常有明显的刺激症状，有畏光、流泪、酸痛等。感染性角膜炎病一般沿三叉神经发病，病变部位侵犯较深，其感觉减退，但因炎症刺激角膜病变的邻近组织，因此刺激症状仍较明显。感染性角膜炎中的病毒性角膜炎病程长，愈后差且易复发，该病常有明显的刺激症状，畏光、流泪、酸痛等，病人常主诉有视物模糊，常可伴有葡萄膜反应，甚至出现虹膜睫状体炎、前房积脓，或继发青光眼，是临床上较为常见的致盲眼病之一。真菌性角膜炎在初期，菌丝在角膜内水平生长，严重时，可穿过角膜后弹力层进入眼内，眼部可出现明显的异物感或刺痛，视力模糊等症状，伴有少量分泌物，角膜病灶处有隆起，形成内皮斑、免疫环、前房积脓等严重的体征。细菌性角膜炎临床症状为病人患眼有畏光、流泪、疼痛、眼睑痉挛、视力障碍等症状随着病情发展，浸润灶迅速扩大，继而形成溃疡，溃疡表面和结膜囊多有脓性分泌物，出现虹膜睫状体炎、角膜穿孔、角膜瘘等并发症。
目前，对于感染性角膜疾病的治疗主要是进行抑制病原体繁殖和缓解炎症对眼部刺激为原则进行治疗。患者可以服用抗病毒或抗菌药物，以及消炎止痛药物进行治疗感染性角膜疾病。重度感染性角膜疾病通常需要进行角膜移植治疗。目前用于治疗感染性角膜疾病的药物主要针对炎症因子，没有恢复角膜上皮功能和特性的功能。因此，寻找即能够高效抑制病原微生物感染引起的免疫应答，又能够恢复角膜上皮功能和特性的治疗药物对临床治疗感染性角膜疾病具有重要意义。
发明内容
本发明的目的在于克服现有技术的不足之处而能够高效一直病原微生物感染引起的免疫应答，同时能够恢复角膜上皮功能和特性的感染性角膜疾病治疗药物YAP/TAZ抑制剂-2在制备预防和/或治疗由病原微生物感染引起的角膜疾病药物中的应用。
为实现上述目的，本发明采取的技术方案为：
第一方面，本发明提供了YAP/TAZ抑制剂-2和/或其衍生物在制备预防和/或治疗由病原微生物感染引起的角膜疾病药物中的应用；所述YAP/TAZ抑制剂-2的化学结构式如下式所示：
本发明首次发现在细胞实验水平和动物实验水平上发现YAP/TAZ抑制剂-2能够有效抵抗由DI引起的角膜损伤。通过细胞实验发现YAP/TAZ抑制剂-2能够激活角膜上皮细胞特性基因的表达，促进角膜上皮细胞分化；通过动物实验发现YAP/TAZ抑制剂-2能够有效缓解角膜上皮细胞病变，维持角膜的透明性和完整性，使角膜的特性和生理功能恢复正常。
作为本发明所述应用的优选实施方式，所述YAP/TAZ抑制剂-2衍生物为YAP/TAZ抑制剂-2在药学上可接受的盐和立体异构体中的至少一种。
第二方面，本发明提供了YAP/TAZ抑制剂-2联合抗角膜损伤药物在制备预防和/或治疗由病原微生物感染引起的角膜疾病药物中的应用。
作为本发明所述应用的优选实施方式，所述抗角膜损伤药物包括笛族化合物、光敏剂、整联蛋白、抗氧化剂、干扰素、黄喋吟衍生物、生长激素、神经营养因子、新血管形成调节剂、抗-VEGF抗体、前列腺素、抗生素、植物性雌激素、抗炎性化合物和抗血管生成化合物中的至少一种。
第三方面，本发明提供了YAP/TAZ抑制剂-2联合抗炎药物和/或抗病原微生物药物在制备预防和/或治疗由病原微生物感染引起的角膜疾病药物中的应用。
作为本发明所述应用的优选实施方式，所述由病原微生物感染引起的角膜疾病为由病原微生物感染引起的角膜上皮细胞损伤疾病。
作为本发明所述应用的优选实施方式，所述由病原微生物感染引起的角膜疾病包括单纯疱疹性角膜炎、牛痘性角膜炎、带状疱疹性角膜炎、丝状角膜炎、镰刀菌属和曲霉菌属真菌性角膜炎、金色葡萄球菌性角膜炎、大肠埃希菌性角膜炎、链球菌性角膜炎、绿脓杆菌性角膜炎、流感嗜血杆菌性角膜炎、奈瑟淋球菌性角膜炎、角膜溃疡和角膜穿孔中的至少一种。
作为本发明所述应用的优选实施方式，所述YAP/TAZ抑制剂-2的有效剂量为生物体每1kg体重施用10-100μg的YAP/TAZ抑制剂-2。
作为本发明所述应用的优选实施方式，所述YAP/TAZ抑制剂-2的有效剂量为生物体每1kg体重施用25-80μg的YAP/TAZ抑制剂-2。
第四方面，本发明提供了一种预防和/或治疗感染性角膜疾病的药物，包括上述的YAP/TAZ抑制剂-2和/或其衍生物、抗角膜损伤药物、抗炎药物和抗病原微生物药物中的至少一种；所述预防和/或治疗感染性角膜疾病的药物还包括药学上可接受的载体。
作为本发明所述药物的优选实施方式，所述感染性角膜疾病的药物的剂型包括片剂、溶液剂、混悬剂、乳剂、微囊、微球、注射液、脂质体和气雾剂中的至少一种。
与现有技术相比，本发明的有益效果为：
1、本发明首次发现在细胞实验水平和动物实验水平上发现YAP/TAZ抑制剂-2能够有效抵抗由DI引起的角膜损伤。通过细胞实验发现YAP/TAZ抑制剂-2能够激活角膜上皮细胞特性基因的表达，促进角膜上皮细胞分化；通过动物实验发现YAP/TAZ抑制剂-2能够有效缓解角膜上皮细胞病变，维持角膜的透明性和完整性，使角膜的特性和生理功能恢复正常。
2、本发明发现YAP/TAZ抑制剂-2的药效较高，且无明显药物毒性可成为临床上治疗感染性角膜疾病的一种强有效的靶点药物。
附图说明
图1为本发明实验例1中各处理组的qRT-PCR技术检测角膜上皮标志物表达水平的统计结果；
图2为本发明实验例1中阴性对照组和模型对照组的qRT-PCR技术检测炎症因子基因表达水平的统计结果；
图3为本发明实验例2中模型对照组的高通量测序中STING通路对应基因表达水平分析结果；
图4为本发明实验例2中阴性对照组和模型对照组的qRT-PCR技术检测促炎症因子表达水平的统计结果；
图5为本发明实验例2中各处理组小鼠的眼球白光及荧光素钠染色结果；
图6为本发明实验例3中各处理组小鼠的内脏器官HE染色结果。
具体实施方式
为更好地说明本发明的目的、技术方案和优点，下面将结合具体实施例对本发明作进一步说明。
下述实验例中所用的试剂、耗材无特别说明均可通过商业途径获得。
YAP/TAZ抑制剂-2购自MCE公司，货号为HY-112921B。
下述实验例中的人角膜组织来源于中山大雪中山眼科中心眼库，已经临床伦理委员会审核，伦理号为2023KPYJ126。
下述实验例中的cGAMP类似物diABZI STING agonist-1trihydrochloride(DI)购自MCE公司，货号为HY-112921B。DI是一种cGAMP类似物，有研究报道cGAS(环化GMP-AMP合酶，Cyclic GMP-AMP Synthase)作为细胞内重要的DNA感受器，会被病毒、细菌和真菌的基因组激活，促进第二信使cGAMP((环化GMP-AMP，Cyclic GMP-AMP)的合成并进一步激活STING(干扰素基因刺激蛋白，Stimulator of interferon genes)，最终诱导I型干扰素产生，从而抵御外来病原生物感染或触发自身炎症反应，是机体固有免疫信号的重要组成。角膜作为免疫豁免组织，当受到病原微生物侵害后，会激活cGAS-STING免疫通路，诱发强烈的炎症反应，持续的免疫应答和炎症反应会损伤角膜上皮，导致角膜上皮细胞异常分化和特性基因表达的丢失，进而破坏角膜稳态，引起角膜散失透明性，是角膜溃疡和穿孔等一系列致盲疾病的诱因之一。DI能够直接结合并诱导STING的磷酸化，从而激活STING及其下游炎症反应，已被广泛用于模拟微生物感染引起的免疫反应和细胞应答中。
下述实验例中的分化培养基购自Gibco，货号为10744019。
下述实验例中的磺丁基醚β-环糊精(SEB-β-CD)购自MCE公司，货号为HY-17031。
下述实验例中所提到的生物学实验均可按照《高通量测序技术》、《分子生物学实验》、《细胞生物学实验》中所提到的实验内容进行操作。
实验例1
为了验证YAP/TAZ抑制剂-2在体外对DI引起的角膜上皮细胞炎症性损伤的修复效果，具体方案如下：
1实验材料及处理
1.1选择人角膜缘组织作为实验对象，将人角膜缘组织依次进行DMEM清洗、剪碎和酶解后种植于铺有10wt％Matrigel的12孔板中于37℃5％CO2的条件下隔天换液培养；
1.2待原代角膜缘干细胞长满后，用0.25％胰蛋白酶-EDTA消化，将重悬的细胞种植于铺有10wt％Matrigel的12孔板中于37℃5％CO2的条件下隔天换液培养；
1.3待上述细胞长满后，吸去角膜缘干细胞培养基，采用PBS清洗一次，将细胞表面残留的血清洗去；
1.4采用分化培养基对角膜缘干细胞进行定向诱导分化，于37℃5％CO2的条件下连续培养7天，每天换液并观察细胞状态，得到高纯度的角膜上皮细胞；除特别注明外，所得角膜上皮细胞的培养条件均为37℃5％CO2。
2试剂的配制
2.1将DI溶解于DMSO中制备为50mM的母液备用；将YAP/TAZ抑制剂-2溶解于DMSO中制备为50mM的母液备用；
2.2将步骤2.1所得DI母液和YAP/TAZ抑制剂-2母液采用培养基分别稀释为10μM的DI工作液和10μM的YAP/TAZ抑制剂-2工作液。
3实验内容
分别设置3个处理组，分别为阴性对照组(DMSO组)、模型对照组(DI组)和实验组(DI+YAP/TAZ抑制剂-2)，按照上述分组分别处理步骤1.4所得角膜上皮细胞，将细胞培养3d，观察细胞变化及利用qPCR技术检测角膜上皮细胞相关蛋白标志物(KRT3、KRT24、CLU、ALDH3A1)和炎症相关基因(CSF3、FGF2、ICAM1、IRAK2、IRAK3、JAK2、TIMP1、白介素家族)的表达，qRT-PCR所采用的引物如表1所示，结果见图1-2。
表1qPCR引物
如图1-2所示，与阴性对照组相比，角膜上皮细胞经DI处理72小时后，角膜上皮标志物KRT3、KRT24、CLU、ALDH3A1的基因表达显著下调，而炎症因子基因(包括CSF3、FGF2、ICAM1、IRAK2、IRAK3、JAK2、TIMP1、白介素家族)的表达显著提高，说明DI能诱导角膜上皮细胞炎症性损伤，本实验造模成功。DI+YAP/TAZ抑制剂-2共处理组的角膜上皮标志物表达水平接近或高于阴性对照组的表达水平，炎症因子基因的表达水平低于模型对照组，表明YAP/TAZ抑制剂-2能明显改善由DI引起的细胞炎症性损伤，使细胞状态恢复，激活角膜上皮细胞特性基因的表达，恢复角膜上皮细胞的功能和特性。
实验例2
为了验证YAP/TAZ抑制剂-2在体内对DI引起的角膜上皮细胞炎症损伤的影响，具体方案如下：
1动物分组
实验对象为4-6周雄性C57/BL6小鼠，本实验共设置3个处理组，分别为阴性对照组CTR(20wt％SBE-β-CD溶液)、模型对照组(DI)和实验组(DI+YAP/TAZ抑制剂-2)。
2试剂配制
将实验例1的步骤2.1中所得DI母液溶解于20wt％SBE-β-CD溶液中，按照动物体重计算，浓度为100μg/kg；将实验例1的步骤2.1中所得YAP/TAZ抑制剂-2母液溶解于20wt％SBE-β-CD溶液中，按照动物体重计算，浓度为40μg/kg。
3实验内容
按照步骤1所述分组分别对小鼠的角结膜注射试剂，在注射后的0、3、5、7和10天分别进行眼球白光和荧光素钠染色拍照；在注射后的第10天对小鼠断颈处死，部分眼球制作组织石蜡切片，进行qPCR表达检测(NFKB1、NFKB2、RELB、JAK2、CXCL1、CXCL2、CXCL3、CXCL4、IL1A、IL1B、IL2RA、IL4RA和IL10)；部分眼球剪取角膜组织提取RNA进行高通量测序。上述检测方法参考文献：dsRNA Induced IFNβ-MMP13 Axis Drives Corneal WoundHealing.Invest Ophthalmol Vis Sci.2022Feb 1；63(2):14.。qPCR检测所采用的引物见表2，高通量测序结果见图3，qPCR结果见图4，眼球白光和荧光素钠染色结果见图5。
表2qPCR所采用的引物及其序列
如图3所示，GO分析显示，模型对照组小鼠的角结膜STING通路被激活后，引起基因的变化富集在与炎症反应、免疫应答相关的生物过程中，横坐标代表显著性检验值，纵坐标代表富集的GO term；如图4所示，模型对照组小鼠的角膜上皮大量促炎症因子(包括NF-κB、JAK2、趋化因子家族和白介素家族)被激活；如图5所示，模型对照组小鼠的角膜上皮受损显著，并随着时间越长，损伤面积越大，上述数据表明注射DI能够成功构建由病原微生物引起的角膜疾病模型。
如图4-5所示，经YAP/TAZ抑制剂-2处理的小鼠角膜上皮促炎症因子表达水平下降，由DI引起的损伤有所缓解，且随着时间越长其恢复效果越好，表明YAP/TAZ抑制剂-2能够改善由DI引起的炎症应答导致的角膜上皮损伤，维持角膜上皮完整性和透明性，使角膜上皮的生理功能恢复正常。
实验例3
为了验证YAP/TAZ抑制剂-2的安全性，实验例2所设置的3个处理组小鼠的内脏进行HE染色观察，具体方案如下：
实验方案与实验例2相似，不同之处为所设置的3个处理组分别为阴性对照组CTR(20wt％SBE-β-CD溶液)、实验组1(YAP/TAZ抑制剂-2)和实验组2(DI+YAP/TAZ抑制剂-2)，其余步骤及参数不变。
对所设置的3个处理组中注射第10天的小鼠进行断颈处死，解剖取出心脏、肝脏、肾脏和肺，进行石蜡切片和HE染色，结果见图6。
如图6所示，无论是单独注射YAP/TAZ抑制剂-2还是同时注射DI+YAP/TAZ抑制剂-2，小鼠的心脏、肝脏、肾脏和肺部组织均正常，未见明显药物毒性，表明YAP/TAZ抑制剂-2具有较好的药物安全性。
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，尽管参照较佳实施例对本发明作了详细说明，本领域的普通技术人员应当理解，可以对本发明的技术方案进行修改或者等同替换，而不脱离本发明技术方案的实质和范围。
Claims (10)
1.YAP/TAZ抑制剂-2和/或其衍生物在制备预防和/或治疗由病原微生物感染引起的角膜疾病药物中的应用；所述YAP/TAZ抑制剂-2的化学结构式如下式所示：
2.如权利要求1所述的应用，其特征在于，所述YAP/TAZ抑制剂-2衍生物为YAP/TAZ抑制剂-2在药学上可接受的盐和立体异构体中的至少一种。
3.YAP/TAZ抑制剂-2联合抗角膜损伤药物在制备预防和/或治疗由病原微生物感染引起的角膜疾病药物中的应用。
4.如权利要求3所述的应用，其特征在于，所述抗角膜损伤药物包括笛族化合物、光敏剂、整联蛋白、抗氧化剂、干扰素、黄喋吟衍生物、生长激素、神经营养因子、新血管形成调节剂、抗-VEGF抗体、前列腺素、抗生素、植物性雌激素、抗炎性化合物和抗血管生成化合物中的至少一种。
5.YAP/TAZ抑制剂-2联合抗炎药物和/或抗病原微生物药物在制备预防和/或治疗由病原微生物感染引起的角膜疾病药物中的应用。
6.如权利要求1-5任一项所述的应用，其特征在于，所述由病原微生物感染引起的角膜疾病为由病原微生物感染引起的角膜上皮细胞损伤疾病。
7.如权利要求6所述的应用，其特征在于，所述由病原微生物感染引起的角膜疾病包括单纯疱疹性角膜炎、牛痘性角膜炎、带状疱疹性角膜炎、丝状角膜炎、镰刀菌属和曲霉菌属真菌性角膜炎、金色葡萄球菌性角膜炎、大肠埃希菌性角膜炎、链球菌性角膜炎、绿脓杆菌性角膜炎、流感嗜血杆菌性角膜炎、奈瑟淋球菌性角膜炎、角膜溃疡和角膜穿孔中的至少一种。
8.如权利要求1-5任一项所述的应用，其特征在于，所述YAP/TAZ抑制剂-2的有效剂量为生物体每1kg体重施用10-100μg的YAP/TAZ抑制剂-2。
9.如权利要求8所述的应用，其特征在于，所述YAP/TAZ抑制剂-2的有效剂量为生物体每1kg体重施用25-80μg的YAP/TAZ抑制剂-2。
10.一种预防和/或治疗感染性角膜疾病的药物，其特征在于，包括权利要求1所述的YAP/TAZ抑制剂-2和/或其衍生物、抗角膜损伤药物、抗炎药物和抗病原微生物药物中的至少一种；所述预防和/或治疗感染性角膜疾病的药物还包括药学上可接受的载体。
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