CN114340606A - 包含自噬激活剂作为活性成分的用于预防或治疗心脑血管疾病的组合物 - Google Patents
包含自噬激活剂作为活性成分的用于预防或治疗心脑血管疾病的组合物 Download PDFInfo
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- CN114340606A CN114340606A CN202080045441.7A CN202080045441A CN114340606A CN 114340606 A CN114340606 A CN 114340606A CN 202080045441 A CN202080045441 A CN 202080045441A CN 114340606 A CN114340606 A CN 114340606A
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Abstract
本发明涉及用于预防或治疗心脑血管疾病的药物组合物,并且可以提供用于预防或治疗心脑血管疾病的药物组合物,其包含至少一种选自化学式1表示的化合物及其药学上可接受的盐作为活性成分。
Description
技术领域
本发明涉及用于预防或治疗心脑血管疾病的药物组合物,更具体地说,涉及使用自噬激活用于预防或治疗心脑血管疾病的药物组合物。
背景技术
自噬作为一种自我消化系统,其中细胞成分被降解并作为营养物和能量来源循环利用,以老化或功能失调的细胞器和受损或错误折叠的蛋白质为目标,并调节维持细胞内稳态和遗传稳定性所必需的蛋白水解过程。自噬还通过再生受损或长寿的线粒体来调节化学代谢和减少活性氧(ROS)的产生,并通过保护细胞免受营养饥饿、氧气耗尽、包括细菌和病毒在内的病原体入侵,以及细胞内和细胞外刺激、如对紫外线的暴露,在维持细胞内环境稳定中发挥中心作用。因此,通过有效诱导自噬,可改善因斑块积聚引起的各种蛋白质病或心脑血管病的症状。
本说明书中引用了大量的论文和专利文件,并给出了引用。通过引用将引用论文和专利文件的公开全部并入本文,以更清楚地描述本发明所属技术领域的水平和本发明的内容。
公开
技术问题
因此,本发明要解决的技术问题是提供用于预防或治疗心脑血管疾病的药物组合物,其通过诱导细胞中的自噬来抑制平滑肌细胞的增殖。
本发明要解决的技术问题还在于提供用于预防或治疗心脑血管疾病的药物组合物,其通过不直接调节血管内皮细胞的表达来抑制平滑肌细胞的增殖并将副作用降至最低。
技术方案
用于解决上述问题的根据本发明实施方案的药物组合物可以是用于预防或治疗心脑血管疾病的药物组合物,其包含一种或多种选自以下化学式1表示的化合物及其药学上可接受的盐作为活性成分。
[化合式1]
在化学式1中,R1为C1-C3烷基,R2和R3各自独立地为氢或卤素,且R2和R3不同时为氢。
如本文所用,术语“烷基”指线性或支链饱和烃基,并且包括例如甲基、乙基、丙基和异丙基。C1-C3烷基指具有具有1-3个碳原子的烷基单元的烷基,并且当C1-C3烷基被取代时不包括取代基中的碳原子数。
如本文所用,术语“卤素”指卤素元素,包括例如氟、氯、溴和碘。
根据本发明的具体实施方案,在化学式1中,R1为C1烷基,且R2和R3为氯。
如本文所用,术语“心脑血管病”是指导致向大脑和心脏供血的血管异常,导致血流速度降低并导致缺血性组织损伤的疾病,是缺血性心脏病、脑血管病、以及高血压、糖尿病、血脂异常和动脉硬化等前期疾病的通称。
可使用本发明组合物预防或治疗的心脑血管疾病包括,例如,心肌梗死、动脉粥样硬化、动脉硬化、动脉粥样硬化血栓形成、冠状动脉疾病、稳定型和不稳定型心绞痛、中风、血管狭窄、血管再狭窄、主动脉瘤,和急性缺血性动脉血管事件,但不限于此。
所述化合物可结合到线粒体电压依赖性阴离子通道-1(VDAC1),并且该化合物可结合到电压依赖性阴离子通道的天冬氨酸12、丙氨酸17、缬氨酸20、组氨酸184和丝氨酸196。
在实施方案中,该化合物可结合到电压依赖性阴离子通道的ATP结合域并抑制电压依赖性阴离子通道的ATP结合域以诱导自噬。
该化合物可通过氢键和与电压依赖性阴离子通道的疏水作用与电压依赖性阴离子通道结合。
该化合物可因结合电压依赖性阴离子通道而诱导自噬以抑制平滑肌细胞的增殖,并且该化合物可因结合电压依赖性阴离子通道而激活细胞中AMP活化蛋白激酶(AMPK)的表达以诱导自噬并抑制细胞生长。
根据本发明用于解决上述另一问题的实施方案的改善心脑血管疾病的功能性食品组合物可包含一种或多种选自以下化学式1表示的化合物及其生物学上可接受的盐作为活性成分。
[化学式1]
由于化学式1表示的并用于本发明的化合物,可通过使用该化合物改善的心脑血管疾病及该化合物的作用机制已在上文中描述,因此将省略这些描述以避免过度重叠。
根据本发明实施方案的用于解决上述另一问题的预防或治疗心脑血管疾病的方法可包括向受试者施用由以下化学式1表示的化合物或其药学上可接受的盐。
[化学式1]
由于化学式1表示的并用于本发明的化合物,可通过使用该化合物改善的心脑血管疾病及该化合物的作用机制已在上文中描述,因此将省略这些描述以避免过度重叠。
根据本发明的一个实施方案,用于解决上述另一个问题的植入人体进行血管成形术的装置可包括药物组合物的衣层,所述药物组合物包含一个或多个选自以下化学式1所示化合物及其药学上可接受的盐作为活性成分。
[化学式1]
由于以上已经描述了由化学式1表示并在本发明中使用的化合物,因此将省略其描述以避免过度重叠。
如本文所用,术语“植入人体用于血管成形术的装置”是指植入人体、具体而言是指由于动脉硬化等血管疾病的血管而机械扩张狭窄或缩窄的血管的医疗装置。用于血管成形术的植入人体的医疗设备包括但不限于支架、导管和网状支架,具体地说是支架。
心脑血管疾病,如动脉粥样硬化,是指脂肪沉积或纤维化在血管内层的疾病。同时,血管再狭窄(restenosis)是血管壁损伤后血管通道狭窄的一种疾病。众所周知,动脉硬化进展和支架植入后发生的血管再狭窄是由于血管平滑肌细胞的增殖和迁移以及细胞外基质的分泌(Cardiovasc.Res.2002,54499-502)。因此,本发明的组合物可高效抑制血管平滑肌细胞的增殖,当涂覆在用于血管成形术的人体植入物(例如支架)上并在体内植入和释放时,可防止再狭窄并实现额外的疾病治疗效果。具体而言,本发明的血管成形术是使用支架的血管成形术。
如本文所用,术语“衣层”意指通过用特定材料修饰目标表面来形成具有特定厚度的新层,并且目标表面和衣层材料可通过离子键或非共价键来修饰。术语“非共价键”是一个概念,不仅包括物理键(如吸附、内聚、纠缠和捕获),还包括相互作用(如氢键和范德华相互作用)单独或与物理键组合作用的键。在本发明中,含有化学式1表示的化合物的衣层可涂覆在血管成形装置(例如支架)上以形成密封层,同时完全包围支架表面或部分密封层。
有利效果
根据本发明的一个实施方案,可以提供一种用于预防或治疗心脑血管疾病的药物组合物,该组合物包含舍曲林以及其药学上可接受的盐,其结合电压依赖性阴离子通道-1(VDAC1),降低细胞质中的ATP水平,并激活AMPK的表达以抑制mTOR表达、诱导自噬和抑制平滑肌细胞(SMC)的生长。
根据本发明的另一个实施方案,可以提供用于改善心脑血管疾病的功能性食品组合物,所述组合物包含舍曲林及其药学上可接受的盐,与传统自噬诱导剂不同,它使用存在于线粒体外膜的电压依赖性阴离子通道-1作为靶蛋白,而不使用mTOR蛋白作为靶蛋白,从而诱导自噬而不直接影响体内其他主要表达,如胰岛素抵抗,这是靶向mTOR蛋白质的抑制剂的缺点。
附图简述
图1A和1B是根据本发明实施方案的药物组合物诱导自噬的实验照片;
图1C是使用MDC荧光染色获得的根据本发明实施方案的药物组合物诱导自噬的照片和图表;
图1D是用于检查根据本发明实施方案的药物组合物对LC3-II和p62的作用的免疫印迹实验的结果;
图1E和1F是图示根据本发明实施方案的药物组合物激活自噬通量的照片;
图2A是图示根据本发明实施方案的药物组合物对使用ATPlite荧光分析系统测量的HUVEC中的细胞ATP水平的影响的结果;
图2B是用于检查根据本发明实施方案的药物组合物是否抑制mTOR/S6K信号传导的免疫印迹实验的结果;
图2C图示了根据本发明实施方案的药物组合物对EGFP-LC3斑点的作用;
图2D图示了根据本发明实施方案的药物组合物的自噬诱导是否涉及mTOR的上游信号通路;
图2E是通过观察根据本发明实施方案的药物组合物对TFEB的核易位而获得的照片;
图2F是用于检测用根据本发明实施方案的药物组合物处理的样品中的自噬诱导的蛋白质印迹的结果;
图3A和3B图示了根据本发明实施方案的药物组合物与小分子结合引起的蛋白质对水解的敏感性的变化;
图3C至3E图示了根据本发明实施方案的药物组合物在蛋白质中的结合位点的照片;
图3F和3G是根据本发明实施方案用于通过药物组合物确定AMPK/mTOR/S6K信号传导调控的起始点的实验的结果;
图3H图示了根据本发明实施方案的药物组合物对VDAC1的活性依赖性;
图4A至4E是关于根据本发明实施方案的药物组合物预防或治疗心脑血管疾病的效果的实验结果;和
图5图示了根据本发明实施方案的通过药物组合物诱导自噬的方法。
发明详述
以下,将参考附图详细描述本发明的优选实施方案。
提供本发明的实施方案是为了向本领域的普通技术人员更完整地解释本发明,可以以各种其他形式修改以下实施方案,并且本发明的范围不限于以下实施方案。提供这些实施方案是为了实现和完成本发明,并向本领域技术人员充分传达本发明的精神。
此外,为了描述的方便和清晰,以下附图中的每层的厚度或尺寸被放大,并且附图中的相同附图标记表示相同的元件。如本文所使用的,术语“和/或”包括一个或多个列举项目的任何一个和任何组合。
本文使用的术语用于描述特定实施方案,但不限制本发明。如本文所使用的,术语“包含”和/或“包括”指定所述形状、数字、步骤、操作、构件、元件和/或组的存在,但不排除一个或多个其他形状、数字、步骤、操作、构件、元件和/或组的存在或添加。
在本说明书中,为了提供用于预防或治疗心脑血管疾病的药物组合物,通过约翰·霍普金斯药物库(JHDL)进行自噬诱导的表型筛选,具有自噬诱导活性的抗抑郁剂(包括舍曲林和吲达曲林)是从该药物库发现的。舍曲林是一种5-羟色胺选择性再摄取抑制剂,1991年在美国因其具有生物活性的药理作用被被批准用作抗抑郁药。在本说明书中,在发现具有自噬诱导活性的候选物质中,已发现具有优异活性的舍曲林(商品名:Zoloft)是用于预防或治疗心脑血管疾病的药物组合物,并将描述药物组合物的自噬诱导活性的详细分子机制及其在自噬相关疾病的临床应用中的潜力。
根据本发明实施方案的用于预防或治疗心脑血管疾病的药物组合物是由化学式1表示的化合物,其中R1为C1烷基,R2和R3为氯,即舍曲林(C17H17Cl2N),其可由以下化学式2表示,以及其药学上可接受的盐。该药物组合物是通过抑制5-羟色胺转运体而具有抗抑郁作用的临床药物。该药物组合物可诱导作为重要自噬标记物的微管相关轻链蛋白3型(LC3-I)转化为LC3-II。LC3转化可能发生在自噬诱导期间或自噬抑制的后期阶段,如自噬体-溶酶体融合或溶酶体降解。此外,该药物组合物可通过诱导自噬抑制平滑肌细胞(SMC)的生长,从而可抑制新血管的生成。因此,认识药物组合物对自噬通量的准确影响是必要的。
[化学式2]
在实施方案中,药物组合物包含一种或多种由化学式1表示的化合物组成的组,由化学式2(舍曲林)表示的化合物及其药学上可接受的盐作为活性成分包括在其中,并可能提供预防或治疗心脑血管疾病的效果。可使用本发明组合物预防或治疗的心脑血管疾病可以是选自以下的疾病:心肌梗死、动脉粥样硬化、动脉硬化、动脉粥样硬化血栓形成、冠状动脉疾病、稳定型和不稳定型心绞痛、中风、血管狭窄、血管再狭窄、主动脉瘤和急性缺血性动脉血管事件,但不限于此。
药物组合物可制备为选自片剂、粉末、胶囊、药丸、颗粒、悬浮液、乳剂、糖浆、气雾剂、外部制剂、栓剂、溶液和注射剂中的任何一种制剂,但不限于此。在另一实施方案中,所述药物组合物可用作皮肤用外部组合物。
在药物组合物中,舍曲林可以药学上可接受的盐的形式使用,并且作为盐形式,使用药学上可接受的游离酸形成的酸加成盐可能是有用的。例如,酸加成盐可从无机酸(例如盐酸、硝酸、磷酸、硫酸、氢溴酸、氢碘酸、亚硝酸或磷酸)和无毒有机酸(例如脂肪族单羧酸和二羧酸盐、苯基取代烷酸盐)、羟基烷酸酯和烷二酸酯、芳香酸、脂肪族和芳香族磺酸中获得。无毒盐可包括硫酸盐、焦硫酸盐、亚硫酸氢盐、亚硫酸盐、亚硫酸氢盐、硝酸盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、盐酸盐、溴化物、碘化物、氟化物、乙酸盐、丙酸盐、癸酸盐、辛酸盐、丙烯酸酯、甲酸盐、异丁酸盐、辛酸盐、庚酸盐、丙酸盐、草酸盐、丙二酸盐、琥珀酸盐、亚硝酸盐、癸二酸盐、富马酸盐、马来酸盐、丁烯-1,4-二甲酸盐、己烷-1,6-二甲酸盐、苯甲酸盐、氯苯甲酸盐、甲基苯甲酸盐、二硝基苯甲酸盐、羟基苯甲酸盐、甲氧基苯甲酸盐、邻苯二甲酸盐、对苯二甲酸盐、苯磺酸盐、甲苯磺酸盐、氯苯磺酸盐、二甲苯磺酸盐、苯乙酸盐、苯丙酸盐、苯丁酸苯酯、柠檬酸盐、乳酸盐、β-羟基丁酸盐、乙醇酸盐、苹果酸盐、酒石酸盐、甲磺酸盐、丙磺酸盐、萘-1-磺酸盐、萘-2-磺酸盐或扁桃酸盐。
根据本发明的酸加成盐可通过常规方法制备,例如,通过将舍曲林溶解在过量的酸水溶液中并使用水溶性有机溶剂(例如,甲醇、乙醇、丙酮或乙腈)沉淀盐。酸加成盐也可通过在水中加热等量的舍曲林和酸或醇,并将混合物蒸发至干或对沉淀盐进行抽滤来制备。
此外,可使用碱制备药学上可接受的金属盐。碱金属或碱土金属盐可通过例如将化合物溶解在过量碱金属氢氧化物或碱土金属氢氧化物溶液中,滤除未溶解的化合物盐,并将滤液蒸发至干来获得。在这种情况下,制备钠、钾或钙盐作为金属盐在药学上是合适的。相应的银盐可通过碱金属或碱土金属盐与合适的银盐(例如硝酸银)反应获得。本发明的药物组合物可包括通过常规方法制备的所有盐、水合物和溶剂化物以及药学上可接受的盐。
在实施方案中,根据本发明的加成盐可通过常规方法制备。具体而言,可通过将舍曲林溶解于水溶性有机溶剂(例如丙酮、甲醇、乙醇或乙腈)中,添加过量的有机酸或无机酸水溶液,然后进行沉淀或结晶来制备加成盐。随后,从混合物中蒸发溶剂或过量酸,然后干燥残渣或对沉淀盐进行抽滤以制备加成盐。
当本发明的药物组合物用作药物时,包含舍曲林和/或其药学上可接受的盐作为活性成分的药物组合物可在临床施用时配制并以各种口服或肠外剂型施用,但不限于此。口服制剂包括片剂、药丸、硬/软胶囊、溶液、悬浮液、乳剂、糖浆、颗粒和酏剂,这些制剂除活性成分外还含有稀释剂,例如乳糖、葡萄糖、蔗糖、甘露醇、山梨醇、纤维素和/或甘氨酸和助流剂,例如二氧化硅、滑石粉、硬脂酸及其镁盐或钙盐和/或聚乙二醇。片剂还可包含粘合剂,例如硅酸镁铝、淀粉糊、明胶、甲基纤维素、羧甲基纤维素钠和/或聚乙烯吡咯烷酮,并且可任选地包含崩解剂或泡腾混合物,例如淀粉、琼脂和海藻酸或其钠盐和/或吸收剂、着色剂、调味剂,还有甜味剂。
在另一实施方案中,包含舍曲林和/或其药学上可接受的盐的药物组合物作为本发明活性成分可经肠外施用。肠外施用可通过皮下注射、静脉注射、肌肉注射或胸腔内注射进行。在这种情况下,为了制备用于肠外施用的制剂,舍曲林和/或其药学上可接受的盐可与稳定剂或缓冲液一起混合在水中,以制备溶液或悬浮液,其可以安瓿或小瓶单位剂型制备。所述组合物可经灭菌和/或含有诸如防腐剂、稳定剂、水合剂或乳化剂、用于调节渗透压的盐和/或缓冲剂和其他治疗上有用物质等辅剂,并且可根据常规方法(例如混合、制粒或包衣)进行配制。
用于人体的本发明药物组合物的剂量可根据患者的年龄、体重、性别、施用形式、健康状况和疾病严重程度而变化,并且基于体重60kg的成年患者,通常为0.001mg/天-1000mg/天,优选0.01mg/天-500mg/天,并且,根据医生或药剂师的判断,该药物组合物可以以固定的时间间隔每天施用一次或几次。
本发明提供一种具有预防或治疗心脑血管疾病效果的准药物组合物,其包含选自舍曲林及其药学上可接受的盐的一种或多种作为活性成分。当本发明的舍曲林用作准药物组合物的活性成分时,舍曲林可以原样加入,或者可以与其他准药物或准药物成分一起使用,并且可以根据常规方法适当地使用。活性成分可根据使用目的以适当的混合量使用。
所述准药物组合物可以颗粒、粉末、溶液、乳膏、软膏、气雾剂、糊剂、凝胶或蜡的形式制备,并且所述溶液可包含所述活性成分,以溶解于溶剂的状态以及悬浮液或乳液的状态。所述配制的准药物的实例包括软膏、贴片、过滤填料、口罩、洗手液、头发制品、湿巾、消毒剂、肥皂或洗涤剂肥皂,并且可以包括常规意义上的所有准药物。
在每种制剂中,可任意选择其他成分并将其混合在具有心脑血管疾病治疗效果的准药物组合物中,优选通过自噬诱导抑制平滑肌细胞(SMC)生长的效果,这取决于其他准药物的制剂或用途。混合的活性成分的量可根据使用目的适当地确定,并且例如,可包含常规辅剂,例如增稠剂、稳定剂、增溶剂、维生素、色素和香料以及载体。基于总重量,所述组合物的含量优选为0.0001%-10%重量,并且当含量超过10%重量时,所述组合物制备期间的稳定性差,并且存在当含量小于0.0001%重量时效果不显著的缺点。
本发明的包含舍曲林作为活性成分的准药物组合物几乎对细胞没有毒性和副作用,因此可用地用作准药物材料。
本发明提供化妆品组合物,其具有预防或治疗心脑血管疾病的效果,优选具有抑制平滑肌细胞(SMC)生长的效果,其包含一种或多种选自舍曲林及其药学上可接受的盐作为活性成分。本发明化妆品组合物中除了包含舍曲林和/或其药学上可接受的盐作为活性成分以外,还包含化妆品组合物中所包含的常用成分,例如,抗氧化剂、稳定剂、增溶剂、维生素、颜料、香料和载体等常规辅剂等成分。
本发明的化妆品组合物可制备成本领域常规制备的任何配方,可配制为例如溶液、悬浮液、乳液、糊剂、凝胶、乳膏、乳液、粉末、肥皂、含有清洁油的表面活性剂、粉底、乳液基、蜡基和喷雾剂,但不限于以上这些。
本发明提供一种具有心脑血管疾病治疗效果、优选抑制平滑肌细胞(SMC)生长效果的保健功能性食品组合物,其包含一种或多种选自舍曲林及其药学上可接受的盐作为活性成分。根据本发明的食品组合物可以根据本领域已知的常规方法制备成各种形式。一般食品可通过将本发明的舍曲林添加到饮料(包括酒精饮料)、水果及其加工食品(例如,水果罐头、罐装食品、果酱和果酱)、鱼、肉及其加工食品(例如,火腿和腌牛肉香肠)、面包和面条(如乌冬、苏巴、拉面、意大利面和通心粉)、果汁、各种饮料、饼干、糖浆、乳制品(如黄油和奶酪)、食用植物油、人造黄油、植物蛋白、干馏食品、冷冻食品和各种调味品(如发酵豆酱、酱油和酱油)中但不限于以上这些来制备。可通过将本发明的舍曲林添加到胶囊、片剂、药丸或类似物中来制备营养补充剂,但不限于此。例如,可通过将本发明的舍曲林本身液化、制粒、胶囊化和粉末化来摄入保健功能食品茶、果汁或饮料(健康饮料),但不限于以上这些。为了以食品添加剂的形式使用本发明的舍曲林,舍曲林可以粉末或浓缩物的形式制备和使用。健康功能性食品组合物可以通过将本发明的舍曲林与已知能有效预防或治疗心脑血管疾病的活性成分混合制备成组合物的形式。
当本发明的舍曲林用作保健饮料时,所述保健饮料组合物可含有各种调味剂或天然碳水化合物作为常规饮料的附加成分。所述天然碳水化合物可为单糖,如葡萄糖和果糖;双糖,如麦芽糖和蔗糖;多糖例如糊精和环糊精;糖醇,例如木糖醇、山梨醇和赤藓糖醇。作为甜味剂,可以使用天然甜味剂,例如甜叶菊素和甜叶菊提取物;合成甜味剂,例如糖精和阿斯巴甜等。天然碳水化合物的比例通常为每100mL本发明组合物约0.01g-0.04g,优选约0.02g-0.03g。
本发明的舍曲林可包含作为具有抗应激、抗抑郁或抗焦虑作用的保健功能性食品的活性成分,且其量为有效实现心脑血管疾病治疗效果的量,且不受特别限制,但优选为0.01%-100%的基于整个组合物的重量。本发明的食品组合物可通过将舍曲林与已知可有效预防或治疗心脑血管疾病的其他活性成分混合来制备。除上述成分外,本发明的保健食品还可含有各种营养素、维生素、电解质、调味剂、着色剂、果胶酸、果胶酸盐、海藻酸、海藻酸盐、有机酸、保护性胶体增稠剂、pH调节剂、稳定剂、防腐剂、甘油、醇或碳酸化剂等。除此之外,本发明的保健食品还可包括:用于生产天然果汁、果汁饮料或蔬菜饮料的果肉。这些成分可以单独使用,也可以混合使用。这些添加剂的比例并不十分重要,但通常每100重量份的本发明组合物在0.01-0.1重量份范围内选择。
本发明可提供植入人体用于血管成形术的装置,所述装置包括含一个或多个选自化学式1表示的化合物及其药学上可接受的盐作为活性成分的衣层,例如支架。本领域技术人员将容易理解,本发明的支架的尺寸可以根据各种病症(例如血管的大小、长度和形状)改变,并且因此也可以适当地改变衣层的厚度。
在实施方案中,可通过喷雾方法将药物组合物涂到支架的表面。所述药物组合物可连续释放一定时间,以治疗可膨胀支架在血管通道中膨胀时引起的血管损伤并防止再狭窄。
所述支架可由例如至少一种选自聚乙交酯、聚乳酸、聚己内酯、碳酸三甲酯、聚羟基烷酸酯、富马酸聚丙烯酯和聚酯的聚合物或其共聚物或其混合物形成。
在下文中,以参考实施例更详细地描述本发明。通过以下实施例,本发明的目的、特征和优点将容易理解。本发明不限于本文描述的实施例,并可以以其他形式实施。提供本文介绍的实施例,以便本发明的精神可以充分传达给本发明所属领域的普通技术人员。因此,本发明不应受到以下实施例的限制。
首先,为了证明根据本发明实施方案的用于预防或治疗心脑血管疾病的药物组合物的自噬诱导以及由此产生的心脑血管疾病治疗效果,进行如下实验。本发明的舍曲林药物组合物是从约翰·霍普金斯药物库(JHDL)获得的2386种化合物中筛选的。
图1A-1G是通过舍曲林诱导自噬的实验照片,舍曲林是根据本发明实施方案的用于预防或治疗心脑血管疾病的药物组合物。图1A和1B说明通过免疫荧光染色观察到的根据本发明实施方案的药物组合物的自噬诱导,图1C是使用MDC荧光染色获得的根据本发明实施方案的药物组合物对自噬空泡的自噬诱导的照片和图表。图1D是用于检查根据本发明实施方案的药物组合物对LC3-II和p62的作用的免疫印迹实验的结果。图1E用于根据E64D的存在或不存在检查根据本发明实施方案的药物组合物的自噬诱导程度,图1F是通过使用GFP和/或mRFP荧光方法观察用根据本发明实施方案的药物组合物处理的样品而获得的照片。图1G是通过使用吖啶橙染色观察根据本发明实施方案的药物组合物的溶酶体活性而获得的结果。
在实施例中,舍曲林诱导的自噬可通过LC3免疫荧光染色证明。参考图1A,在未处理样品的对照组(对照组)、用吲达曲林处理样品的实验组(吲达曲林)和用本发明的药物组合物舍曲林处理样品的实验组(舍曲林)上进行LC3免疫荧光染色的结果,可以看出,用舍曲林处理的细胞也在细胞质中诱导LC3,与吲达曲林处理的情况相似,吲达曲林已知为抗抑郁剂并诱导非选择性单胺转运体抑制剂的自噬。参考图1B,是测量细胞质中LC3诱导量的结果,施用0.1μM、2μM或5μM舍曲林的样品,未施用舍曲林样品作为对照组,结果可以看出,LC3在细胞质中的诱导与舍曲林的剂量成比例。
在实施例中,舍曲林自噬的诱导作用可以通过用荧光染料的单丹酰尸胺(MDC)染色自噬空泡来研究,该荧光染料与自噬空泡结合。参考图1C,在对照组(对照组)中观察到LC3表达,其中自噬空泡未经任何药物组合物处理,经吲达曲林处理细胞(吲达曲林),经舍曲林处理细胞(舍曲林),可以看出,经吲达曲林处理的细胞和经舍曲林处理的细胞均表达LC3。通过对经吲达曲林处理的细胞和经舍曲林处理的细胞进行MDC染色,已经证实,经舍曲林处理的细胞中表达的LC3数量约为经吲达曲林处理的细胞中表达的LC3数量的1.5倍。换言之,可以看出舍曲林对自噬空泡的自噬诱导作用明显优于吲达曲林。
为了研究药物组合物是否触发蛋白质转换和自噬的运动,使用了各种可用的方法来检测自噬降解和监测自噬通量。首先,通过基本的时间依赖性免疫印迹法测量LC3-II和p62水平,作为检查多少自噬底物以溶酶体依赖性方式降解的方法。由于LC3-II和p62仅在自噬过程中选择性降解,因此其降解被广泛用于评估自噬通量。
参考图1D,在使用舍曲林(根据本发明实施方案的药物组合物)治疗(舍曲林)的情况下,可以看到LC3-II和p62的水平在24小时内迅速增加,在48小时达到峰值,然后从72小时开始下降。这表明LC3-II和p62蛋白的降解发生在自噬的后期。另一方面,在V-ATPase抑制剂巴弗洛霉素A的情况下(Baf),观察到LC3-II和p62的水平在24小时内增加,并且两种蛋白质的高水平在72小时的后处理时间内保持。这是因为巴弗洛霉素A抑制自噬通量。因此已证实本发明的药物组合物诱导自噬。
在另一个实例中,研究了在存在和不存在溶酶体蛋白酶抑制剂E64D的情况下,药物组合物舍曲林对LC3-II水平的影响。如果用药物组合物处理导致LC3-II的正常通量状态,则与仅用蛋白酶抑制剂处理的情况相比,在同时用药物组合物和溶酶体蛋白酶抑制剂处理的情况下,LC3-II的表达可能进一步增加。
参考图1E,当使用E64D和根据本发明实施方案的药物组合物一起处理的情况(图1E中右侧的舍曲林)与仅使用药物组合物处理的情况(图1E中左侧的舍曲林)进行比较时,在同时使用药物组合物和E64D处理的情况下,LC3-II水平进一步增加,这表明药物组合物激活自噬通量。另一方面,在巴弗洛霉素A的情况下(Baf),无论E64D是否存在,LC3-II的表达水平相似。因此,可以看出,作为本发明的药物组合物的舍曲林在同时使用舍曲林和蛋白酶抑制剂处理的情况下进一步增加自噬通量的活性。
基于mRFP-LC3和GFP-LC3之间不同的pH稳定性,为了使从中性自噬体到酸性自噬体的变化可视化,可以使用带有mRFP/McHery GFP双标记的LC3。mRFP的荧光在rososome中相对稳定,而GFP的荧光在酸性物质中不稳定。因此,通过观察自噬体的绿色和红色荧光在局部区域减少,自噬体的红色荧光增加,可以证实自噬通量。参考图1F,用巴弗洛霉素A、吲达曲林或舍曲林处理的样品用GFP、mRFP或GFP和mRFP处理,当样品用舍曲林处理时,红色荧光(R值=0.517)增加,舍曲林是根据本发明实施方案的药物组合物,但黄色荧光(R值=0.943)可在用巴弗洛霉素A处理样品时在HUVEC中累积。因此,可以看出,作为本发明的药物组合物的舍曲林显著诱导自噬。
在实施例中,使用吖啶橙染色法研究溶酶体活性,这是一种研究溶酶体作用和可靠性的分析方法。参考图1G,用舍曲林处理显著增加吖啶橙的密度,这表明舍曲林通过激活溶酶体活性诱导自噬通量。通过这些结果,已证实根据本发明实施方案的药物组合物激活自噬通量。
为了表征药物组合物诱导自噬所涉及的信号通路,研究了对典型通路的影响。AMPK-mTOR典型通路可能因产生的细胞能量不足而被激活,并诱导自噬。图2A是说明根据本发明实施例的药物组合物对使用ATPlite发光分析系统测量的HUVEC中细胞ATP水平的影响的结果。
参考图2A,在使用药物组合物处理0-360分钟的情况下,可以看到细胞内ATP水平随时间成比例降低。细胞内AMP-ATP比率的增加依次激活AMPK通路。通过测量经雷帕霉素、吲达曲林或舍曲林处理的样品中的p-AMPK/AMPK比率,可以看出,与经雷帕霉素处理的样品相比,经吲达曲林或舍曲林处理的样品中观察到相对较高的p-AMPK/AMPK,这表明AMPK途径被激活。
图2B是用于检查根据本发明实施方案的药物组合物是否抑制mTOR/S6K信号传导的免疫印迹实验的结果。参考图2B,可以看出药物组合物通过诱导AMPK活性和降低mTOR及其下游S6K的磷酸化水平来抑制信号传导。具体而言,这可以通过以下事实得到证实:使用舍曲林治疗的p-mTOR/mTOR的相对比率低于使用雷帕霉素或吲达曲林治疗的情况。然而,可以看出,AMPK的磷酸化水平不受影响,mTOR的磷酸化直接受到抑制,因此在雷帕霉素处理的情况下,S6K的磷酸化也受到抑制。因此,所述药物组合物的作用不同于用雷帕霉素处理的情况,并且该药物组合物可诱导AMPK的扩增以抑制AMPK下游的mTOR和S6K的信号传导。
图2C是通过观察舍曲林(根据本发明实施方案的药物组合物)对EGFP-LC3斑点的作用而获得的照片。参考图2C,可以看出,雷帕霉素诱导的自噬不受化合物C处理的显著影响,但通过化合物C和舍曲林联合处理,细胞基质中的EGFP-LC3斑点显著减少。
图2D是观察到作为根据本发明实施方案的药物组合物的舍曲林的自噬诱导涉及mTOR的上游信号通路的结果的照片和图表。为了研究舍曲林诱导的自噬涉及mTOR的上游信号通路,在舍曲林处理前1小时制备了自噬抑制剂,包括PI3K抑制剂的3-MA、PI3K/AKT抑制剂的渥曼青霉素和MEK/ERK抑制剂的PD98059。参考图2D,可以看出,尽管存在每种自噬抑制剂,EGFP-LC3阳性斑点仍保留在细胞基质中。这一结果表明舍曲林诱导的自噬不调节PI3K/AKT和MEK/ERK信号通路。
最近,作为自噬诱导和溶酶体生物发生的主要调节因子的转录因子EB(TFEB),已知其与mTOR信号通路相联系。当mTOR被激活并通过形成V-ATP酶/调节因子Rag蛋白复合物显示其在溶酶体表面的位置时,形成的蛋白复合物可以磷酸化TFEB,抑制TFEB的核易位,并阻止靶染色体的表达。
图2E是通过用增强型绿色荧光蛋白(EGFP)-TFEB质粒感染HUVEC直接观察TFEB的核易位而获得的照片,以研究根据本发明实施方案的药物组合物操作由于从蛋白质复合物分离mTOR导致的TFEB易位。参考图2E,可以看出,在使用药物组合物处理2至24小时期间未检测到TFEB的核易位,但已知为TFEB和自噬的小分子诱导剂的MSL诱导HUVEC中TFEB的核易位。因此,根据本发明实施方案的药物组合物抑制TFEB的磷酸化,实现TFEB的核易位,并因此可激活靶染色体的表达。
图2F是经根据本发明实施方案的药物组合物处理的样品中用于检查自噬诱导的蛋白质印迹的结果照片。在实验中,用DMSO、雷帕霉素或药物组合物舍曲林以图2F中所述的各自浓度处理野生型Hela细胞和不含TFEB的Hela细胞,并对细胞提取物进行蛋白质印迹分析以检查自噬。参考图2F,用药物组合物处理在TFEB+/+和TFEB-/-HeLa细胞诱导转化成LC3-II。这表明该药物组合物以不依赖于TFEB的方式诱导自噬。
由于线粒体通过氧化磷酸化在ATP生产中发挥重要作用,并且药物组合物独立于PI3K/AKT和MEK/ERK信号通路激活自噬,因此电压依赖性阴离子通道-1(以下简称VDAC1)是存在于线粒体外膜中的通道,被选为舍曲林的候选靶材料。已知VDAC1通过转运ATP在细胞代谢中发挥重要作用,其他小的代谢物通过线粒体外膜与TOR活性相关。
最近,伊曲康唑作为VDAC1的小分子拮抗剂被发现是血管生成的主要抑制剂,因为伊曲康唑控制AMPK/mTOR信号轴。为了研究VDAC1和舍曲林之间的直接相互作用,应用了药物亲和反应靶点稳定性(DARTS)分析。
图3A是说明蛋白质对水解的敏感性的变化的结果,该变化是由根据本发明实施方案的药物组合物与小分子的结合引起的。使用DARTS方法观察水解敏感性的变化,DARTS方法是一种使用蛋白质与小分子结合引起的水解敏感性变化用于靶点识别和验证的无标记检测方法。参考图3A,可以看出,当VDAC1和β-肌动蛋白用舍曲林处理,然后添加链霉蛋白酶时,VDAC1表现出更高的稳定性,但β-肌动蛋白(一种与舍曲林没有结合亲和力的蛋白质)被链霉蛋白酶降解,因为其对蛋白水解的敏感性不会因舍曲林的处理而改变。
图3B是说明蛋白质对水解敏感性的变化的结果,该变化是由根据本发明实施方案的药物组合物与另一小分子的结合引起的。在本实验中,使用5-羟色胺再摄取转运体(SRT)蛋白进行DARTS分析,该蛋白是舍曲林与抗抑郁活性相关的已知靶蛋白。舍曲林诱导的5-羟色胺再摄取转运体蛋白脱敏可能验证了纳摩尔浓度。参考图3B,在纳摩尔浓度下,舍曲林在20分钟或更长时间内增加5-羟色胺再摄取转运蛋白的链霉蛋白酶的稳定性,但不增加VDAC1的稳定性。因此,本发明的药物组合物(舍曲林)对5-羟色胺再摄取转运(SRT)蛋白的结合亲和力可能大于对VDAC1的结合亲和力。
然而,这可能证实舍曲林直接与细胞内VDAC1结合。图3C-3E是图示根据本发明实施方案的药物组合物在蛋白质中的结合位点的照片。参考图3C,舍曲林的ATP和DID可在最稳定状态下在α-螺旋和β折叠之间结合到VDAC1,并且结合基序被描绘为舍曲林和VDAC1口袋之间的高亲和力相互作用。图示氢键表面的灰色条表示配体,橙色表示疏水相互作用,紫色表示静电相互作用,绿色和浅蓝色表示氢键合。
参考图3D和3E中,可以看出VDAC1和舍曲林之间的氢键合(H184,S196)和疏水相互作用(A17,V20)赋予VDAC1高结合强度,如同VDAC1抑制剂ATP(d)和DIDS(e)。优选地,药物组合物可结合到VDAC1的ATP结合域,VDAC1为电压依赖性阴离子通道,并且可结合到ATP结合域的天冬氨酸12、丙氨酸17、缬氨酸20、组氨酸184和丝氨酸196。因此,结合到ATP结合域的药物组合物可通过抑制ATP结合域在细胞中诱导自噬。
图3F和3G是用于检查根据本发明实施方案的药物组合物对AMPK/mTOR/S6K信号传导的调制是否通过直接结合到VDAC1开始的实验的结果。在本实验中,使用VDAC1野生型和VDAC1-/-MEF(小鼠胚胎成纤维细胞),且野生型(WT MEF)和不含VDAC1的MEF(VDAC1-/-MEF)均用雷帕霉素(Rapa)和舍曲林(舍曲林)处理。参考图3F,可以看出舍曲林在野生型MEF中显著激活AMPK并抑制mTOR/S6K磷酸化。另一方面,可以看出,在没有VDAC1的MEF中,无论VDAC1表达如何,雷帕霉素仍然抑制mTOR活性,但舍曲林不调节AMPK/mTOR/S6K信号。参考图3G,在使用舍曲林处理的情况下,与野生型MEF相比,无VDAC的MEF中EGFP-LC3斑点显著减少。
图3H是用于说明根据本发明实施方案的药物组合物对VDAC1的活性依赖性的结果。参考图3H,用舍曲林处理细胞48小时,并评估细胞增殖和线粒体活性。可以看出,野生型MEF的细胞增殖持续受到舍曲林的抑制,但当舍曲林以约10μM的量大量施用于不含VDAC1的MEF时,细胞增殖在72小时维持在50%或以上。因此,VDAC1可能是舍曲林调节AMPK/mTOR/S6K信号传导和自噬诱导活性的生物学相关靶蛋白。
图4A-4E是关于根据本发明实施方案的药物组合物的心脑血管疾病治疗效果的实验结果。自噬的药理学调节策略是血管疾病的重要途径。例如,由平滑肌细胞(SMC)的异常细胞增殖引起的再狭窄以及由斑块形成引起的巨噬细胞聚集和血管狭窄是典型的自噬相关血管疾病。自噬诱导可抑制平滑肌细胞的快速增殖,激活胆固醇和胆固醇酯的酸水解,从而抑制巨噬细胞中胆固醇的脱落和泡沫细胞的形成。最近的再狭窄治疗方法依赖于支架植入术、血管成形术或放射治疗,且有限的药物得到了研究。
为了研究本发明药物组合物对再狭窄的药物作用,研究了药物组合物对平滑肌细胞(SMC)中细胞扩增和自噬诱导活性的影响。用药物组合物舍曲林处理细胞72小时,并评估细胞增殖和线粒体活性。
图4A图示了根据本发明实施方案的用于治疗心脑血管疾病的药物组合物的平滑肌细胞增殖抑制作用。用MTT色度分析法测定用药物组合物在0μM-20μM下处理72小时后的细胞生长。参考图4A,可以看出,随着施用的药物组合物的量从0μM增加到20μM,平滑肌细胞的增殖受到更大的抑制。因此,药物组合物抑制平滑肌细胞的增殖取决于所述剂量。
图4B图示了根据本发明实施方案的药物组合物对细胞内LC3-II和p62水平的影响。用药物组合物处理平滑肌细胞(SMC)24小时后,测量LC3-II和p62水平。参考图4B,使用药物组合物舍曲林处理可显著增加LC3-II和p62水平,与雷帕霉素常规处理的情况一样,与处理浓度成比例。然而,可以看出,β-肌动蛋白不受雷帕霉素或舍曲林处理的影响。
图4C图示了用于检查根据本发明实施方案的药物组合物对溶酶体的吸收的吖啶橙染色的结果。样品分别用5μM药物组合物、5μM吲达曲林、10μM巴弗洛霉素A和10μM雷帕霉素处理24小时。细胞在固定前用2μg/mL的吖啶橙处理20分钟。固定细胞后,用共聚焦显微镜检查样品,标尺为10μm。参考图4C,可以看出,经药物组合物处理的样品的吖啶橙荧光强度增加,并且比经雷帕霉素或吲达曲林处理的样品的吖啶橙荧光强度更强。因此,本发明的药物组合物可通过激活平滑肌细胞(SMC)中的溶酶体有效诱导自噬通量。
图4D是图示根据本发明实施方案的药物组合物的心脑血管疾病治疗效果的照片。为了研究该药物组合物对心脑血管疾病的治疗作用,采用小鼠颈动脉再狭窄模型。图中Y轴表示新内膜斑决面积与内部器官面积的百分比,这可以表明新内膜的积聚程度。
在实施例中,小鼠模型的内血管区域(经动脉切开后未经处理)(上部照片之间的左侧对照照片)和小鼠模型的内血管区域(经动脉切开后经2μM浓度的本发明药物组合物处理)(上部照片之间的右侧舍曲林照片)进行拍照。参考图4D,可以看到施用浓度为2μM的药物组合物的小鼠模型的新内膜层减少。已经证实该药物组合物可以有效抑制平滑肌细胞的新内膜膜的积聚。
图4E是用于检查根据本发明实施方案的药物组合物对细胞凋亡的影响的TUNEL染色的结果。其中进行动脉切开然后未进行处理的小鼠模型样本(对照组)及动脉切开然后用本发明的药物组合物进行处理的小鼠模型样本(舍曲林)进行TUNEL标记。可使用TUNEL标记法检测样品中的细胞凋亡。
参考图4E可以看出,在使用本发明的药物组合物处理的样品中,细胞凋亡没有显著发生。因此,本发明的药物组合物可以有效抑制新血管的生成而不影响细胞凋亡。在这种情况下(未图示)用雷帕霉素处理动脉切开的小鼠模型,有抑制平滑肌细胞增殖从而改善血管疾病症状的作用,但伴随该作用发生约30%的凋亡。然而,在用本发明药物组合物处理的小鼠模型中未诱导凋亡。因此,由本发明的药物组合物诱导的自噬可独立且有效地仅抑制新血管的生成,而不会因凋亡而引起细胞内毒性。
尽管临床药物库中基于表型的筛选可能是有效的,但小分子的翻译对于自噬相关疾病的治疗对于建立小分子活性的主要机制非常重要。舍曲林是根据本发明实施方案的药物组合物,是经批准用作抗抑郁剂的选择性5-羟色胺转运体抑制剂。通过本说明书已阐明舍曲林是诱导自噬的主要物质。具体而言,在DARTS分析中,纳摩尔浓度的舍曲林足以与5-羟色胺再摄取转运体结合,但不会诱导自噬。
图5图示了根据本发明实施方案的通过药物组合物诱导自噬的方法。为了阐明舍曲林诱导自噬的分子机制,对线粒体外膜蛋白和舍曲林新靶蛋白VDAC1进行了研究。参考图5和上述实验实施例和实施例,作为根据本发明实施方案的药物组合物的舍曲林可通过结合VDAC1、降低细胞内ATP水平、激活AMPK和抑制mTOR来诱导自噬。所述药物组合物可通过舍曲林诱导自噬有效抑制心脑血管疾病,例如动脉硬化和再狭窄。
为了在没有化学修饰的情况下鉴定小分子的靶蛋白,采用了无标记的方法,DARTS。通过系统靶点识别,包括DARTS蛋白质印迹分析、计算机模拟和使用去除VDAC1的细胞进行的实验,可以看出VDAC1是舍曲林诱导自噬激活的生物学相关靶点。
伊曲康唑和DIDS等小分子抑制剂对VDAC1的药物抑制可能表明VDAC1与线粒体代谢之间存在表型关联。抑制VDAC1可能阻止Ca2+介导的氧化应激和细胞凋亡。根据本发明实施方案的药物组合物在结构上类似于吲达曲林,但经历了相对较高程度的磷酸化,因此可比吲达曲林更紧密地与VDAC1相互作用。因此,该药物组合物在HUVEC和SMC中的自噬和抗增殖作用方面可能提供优于吲达曲林的生物活性。
在另一实施例中,已将VDAC1识别为根据本发明用于诱导自噬的实施方案的药物组合物的主要靶点。
通过舍曲林调节VDAC1的自噬以及通过本发明的药物组合物产生的独立于凋亡的效应可应用于无细胞毒性的自噬治疗。VDAC1作为舍曲林靶蛋白的鉴定不仅促进了自噬相关疾病新治疗物质的开发,而且可能为阐明VDAC1在自噬信号和自噬相关疾病中的作用提供新的化合物研究。
上述本发明不限于上述实施方案和附图,并且对于本发明所属领域的普通技术人员来说,可以在不脱离本发明的技术精神的情况下进行各种替换、修改和变化。
Claims (14)
2.根据权利要求1的药物组合物,其中在化学式1中R1为C1烷基且R2和R3为氯。
3.根据权利要求1的药物组合物,其中所述心脑血管疾病选自心肌梗死、动脉粥样硬化、动脉硬化、动脉粥样硬化血栓形成、冠状动脉疾病、稳定型和不稳定型心绞痛、中风、血管狭窄、血管再狭窄、主动脉瘤、急性缺血性动脉血管事件。
4.根据权利要求1的药物组合物,其中所述化合物与线粒体电压依赖性阴离子通道-1(VDAC1)结合。
5.根据权利要求4的药物组合物,其中所述化合物与所述电压依赖性阴离子通道的天冬氨酸12、丙氨酸17、缬氨酸20、组氨酸184和丝氨酸196结合。
6.根据权利要求4的药物组合物,其中所述化合物与电压依赖性阴离子通道的ATP结合域结合,并抑制所述电压依赖性阴离子通道的ATP结合域以诱导自噬。
7.根据权利要求4的药物组合物,其中所述化合物通过氢键和与电压依赖性阴离子通道的疏水相互作用与所述电压依赖性阴离子通道结合。
9.根据权利要求8的功能性食品组合物,其中在化学式1中R1为C1烷基且R2和R3为氯。
10.根据权利要求8的功能性食品组合物,其中所述心脑血管疾病选自心肌梗死、动脉粥样硬化、动脉硬化、冠状动脉疾病、稳定型和不稳定型心绞痛、中风、血管狭窄、血管再狭窄、主动脉瘤、和急性缺血性动脉血管事件。
12.根据权利要求11的方法,其中在化学式1中,R1为C1烷基且R2和R3为氯。
14.根据权利要求13的装置,其中在化学式1中,R1为C1烷基且R2和R3为氯。
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