CN113648309B - 一种小分子化合物在制备帕金森病中药物的应用 - Google Patents
一种小分子化合物在制备帕金森病中药物的应用 Download PDFInfo
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Abstract
本发明涉及一种小分子化合物在制备帕金森病中药物的应用。本发明的小分子化合物ChemJ可以通过促进DJ‑1的表达,降低帕金森病的氧化应激水平,而达到保护多巴胺能神经元的效果。因此,ChemJ可能被制作成一种新的帕金森病的疾病修饰治疗药物。
Description
技术领域
本发明属于生物医药领域,特别涉及一种小分子化合物在制备帕金森病中药物的应用。
背景技术
帕金森病(Parkinson's disease,PD)是第二常见的神经退行性疾病,其患病率与年龄呈正相关,临床表现既有静止性震颤、运动迟缓、肌强直、姿势步态异常等运动症状,也有嗅觉减退、自主神经功能异常、睡眠障碍、精神异常等非运动症状,这些症状长期且严重影响患者的工作能力与生活质量。截至2016年,全球PD患者数量已经超过610万人,中国达到300万人。特别在老龄化加剧的国家与地区,PD患者的数量将继续增加,这将造成沉重的社会负担。
PD的主要病理特征是中脑黑质部位的多巴胺能神经元丢失,伴随Lewy小体形成。目前临床上常用的PD治疗药物大多靶向多巴胺通路,可缓解临床症状,但不能阻止PD的病程进展,甚至有较明显的副作用。
(1)左旋多巴。补充缺失的神经递质多巴胺水平。副作用:疗效减退、症状波动、异动症、厌食、心动过速、室性早搏等。
(2)多巴胺受体激动剂(Pramipexole、Ropinirole、Rotigotine等)。增强神经元对多巴胺的反应性,以代偿多巴胺能功能减退或缺失。副作用:厌食、消化不良、幻觉、嗜睡、强迫行为等。
(3)儿茶酚-O位-转移酶(COMT)抑制剂(tolcapone、entacapone、Opicapone)。抑制多巴胺的降解,配合左旋多巴使用。副作用:加重左旋多巴的副作用、肝损、影响睡眠等。
(4)单胺氧化酶B抑制剂(Selegiline、Rasagiline、safinamide)。抑制多巴胺的降解,可能有一定的神经保护作用(这一点仍有待更多临床试验验证)。副作用:加重左旋多巴的副作用、谵妄、幻觉、焦虑、失眠、直立性低血压等。
除此以外,已经有一些PD的新药开发工作,它们主要集中在靶向SNCA与LRRK2的药物上。不过,PD是一种异质性的疾病,针对单一靶点的药物未必能解决所有PD患者的问题。
靶向α-synuclein的新药的策略是抑制α-synuclein的沉积,以改善PD的症状。具体方法包括抗体、疫苗、小分子化合物等。在PD的转基因小鼠模型上观察到这些药物对PD运动症状得到改善,而相应的临床试验还在进行中。然而,这一策略也存在着一些问题:α-synuclein的沉积是导致了PD的根本原因还是伴随现象?选择何种形式的α-synuclein作为治疗靶点?由于α-synuclein也具有一些生理功能,那么抑制α-synuclein是否会因为干扰其生理功能而产生副作用?这些问题,需要对α-synuclein的作用有更深入的了解。
靶向LRRK2的新药的策略是抑制LRRK2的激酶活性。在PD的小鼠模型中,可观察到LRRK2抑制剂起到了减少α-synuclein沉积以及神经保护的作用,而相应的临床试验也在进行中,然而目前的困难是缺少LRRK2的活性检测方法,而且很难招募到足够的LRRK2相关的PD患者。
由此可见,在开发新的PD疾病修饰治疗药物,尤其是针对其它靶点的药物,仍然是当前亟需开展的工作。
发明内容
本发明所要解决的技术问题是提供一种小分子化合物在制备帕金森病中药物的应用,该小分子化合物的靶点为DJ-1,有望弥补现有PD治疗药物的局限。
本发明提供了一种小分子化合物在制备帕金森病中药物的应用,所述小分子化合物的结构式为:以下记为chemJ。
所述药物的靶点为DJ-1。
所述药物包括小分子类化合物及药学上可用的辅料。
进一步的,所述辅料包括填充剂、黏结剂、润滑剂、分散剂、助流剂、润湿剂、崩解剂、香料或色料。
所述药物的剂型为口服剂或注射剂。
进一步地,所述口服剂的形式包括片剂、硬或软胶囊、锭剂、滴丸、微丸、水性或油混悬剂、乳剂、散剂、颗粒剂、口服液或糖浆剂。
进一步地,所述注射剂的形式为:灭菌的水性或油性溶液、无菌粉末、脂质体、乳剂或微囊。
有益效果
本发明的小分子化合物ChemJ可以通过促进DJ-1的表达,降低帕金森病的氧化应激水平,而达到保护多巴胺能神经元的效果。因此,ChemJ可能被制作成一种新的帕金森病的疾病修饰治疗药物。此外,由于DJ-1在炎症性肠病(inflammatory bowel disease,IBD)中也起到了抵抗氧化应激、抑制凋亡的保护作用,因此理论上ChemJ可以通过提高肠道的DJ-1表达而起到改善IBD的治疗效果。
附图说明
图1为小分子化合物的筛选策略。
图2为小分子化合物的筛选流程。
图3为验证小分子化合物ChemJ对DJ-1表达的作用;其中,A为ChemJ的化学结构式;用Western blot检测DJ-1的表达量,以α-tubulin作为内参,B为使用0.25μM至5μM浓度的ChemJ处理SH-SY5Y细胞系;C为使用0.1μM至2.5μM浓度的ChemJ处理小鼠原代大脑皮层神经元。*p<0.05,单因素方差分析-多重比较检验。
图4为检测超氧阴离子(O2 -)与活性氧(ROS),以判断小分子化合物ChemJ对MPP+处理SH-SY5Y的PD细胞模型中的氧化应激水平的干预作用;其中,A为在0.5mM的MPP+处理SH-SY5Y细胞6小时之后给予1μM的ChemJ处理24小时;B为使用1μM的ChemJ处理SH-SY5Y细胞24小时后,给予0.5mM的MPP+处理2小时;Ctr:未加MPP+;DMSO:不含化合物的0.1%浓度DMSO溶剂处理;J:1μM的ChemJ处理。*p<0.05,**P<0.01,单因素方差分析-多重比较检验。
具体实施方式
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。此外应理解,在阅读了本发明讲授的内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
高通量药物筛选阶段所使用的8000个小分子化合物,皆源自ChemDiv公司的未成药小分子化合物库。所使用的ChemJ委托MCE公司合成。
实施例1
在前期工作中,分别从转录水平、转录后水平探究了DJ-1的表达调控机制[Tan Y,Wu L,Li D,Liu X,Ding J,Chen S.Methylation status of DJ-1in leukocyte DNA ofParkinson’s disease patients.Transl Neurodegener.2016;5:5.doi:10.1186/s40035-016-0052-6];[Chen Y,Gao C,Sun Q,Pan H,Huang P,Ding J,et al.MicroRNA-4639is aregulator of DJ-1expression and a potential early diagnostic marker forParkinson’s disease.Front Aging Neurosci.2017;9:1-9.doi:10.3389/fnagi.2017.00232]。在此基础上,本实施例构建了基于DJ-1启动子活性的荧光素酶报告系统,以筛选能促进DJ-1表达的小分子化合物(见图1)。
所述荧光素酶报告系统的制备方法包括:
(1)将DJ-1启动子片段插在荧光素报告质粒“pLuc0”(该质粒由中国科学院神经科学研究所徐进教授提供)的luciferase基因之前,使得荧光素酶基因的表达受到DJ-1启动子的活性调控。质粒上具有Neo基因,故具有G418抗性。
(2)使用lipofectamine2000(购于ThermoFischer公司)将该质粒转染至SH-SY5Y细胞(该细胞株购于中科院细胞库)中,并通过G418获得稳定表达上述报告的细胞株,作为药物筛选的报告系统。
(3)将这种细胞株接种至384孔板中,经小分子化合物处理24小时后,加入一种长半衰期荧光素酶底物Steady-Glo(购于Premega公司),与细胞中的荧光素酶反应并发光,发光强度反映了DJ-1启动子的活性。使用酶标仪检测各处理组的发光强度,结合阴性对照组(不含化合物的溶剂处理)作分析。
在国家化合物样品库进行了8000个未成药的小分子化合物的初筛工作,再经过复筛验证,得到11个候选化合物(见图2)。为了验证这些化合物是否能有效地提高DJ-1的表达,选取了能够获得的8个化合物,分别处理SH-SY5Y细胞系,通过Westernblot检测DJ-1蛋白表达量。其中ChemJ促进DJ-1蛋白表达的效果最为明显,在1μM至2μM浓度的ChemJ处理时,DJ-1的表达量达到了溶剂对照组的2倍左右(见图3B)。此后使用ChemJ处理小鼠的原代神经元,得到了类似的结果,即在0.25μM至0.5μM浓度的ChemJ处理时,DJ-1的表达量达到了溶剂对照组的2倍左右(见图3C)。
为了验证ChemJ对于PD的过度氧化应激是否有缓解作用,选用了MPP+刺激SH-SY5Y的PD氧化应激细胞模型来作验证。结果显示,无论是在造模后给予ChemJ处理,还是造模前给予ChemJ处理,均能缓解氧化应激的水平(见图4)。
目前在帕金森病的MPP+细胞模型中,本发明是采用含有1μM或其它浓度的ChemJ的培养液处理SH-SY5Y细胞系。其中,先使用DMSO作为溶剂配制10mM的溶液,在此基础上可继续用DMSO稀释成1mM或其它浓度的溶液。此后,可用相应的细胞培养液(如DMEM+10%胎牛血清)稀释1000倍,配成终浓度为1μM或其它浓度的ChemJ培养基,以更换培养液的方式处理细胞。
上述这些结果提示,小分子化合物ChemJ可以增加DJ-1蛋白的表达,并减轻PD的过度氧化应激。
Claims (7)
1.一种小分子化合物在制备治疗帕金森病的药物中的应用,其特征在于:所述小分子化合物的结构式为:
2.根据权利要求1所述的应用,其特征在于:所述药物的靶点为DJ-1。
3.根据权利要求1所述的应用,其特征在于:所述药物包括小分子化合物及药学上可用的辅料。
4.根据权利要求3所述的应用,其特征在于:所述辅料包括填充剂、黏结剂、润滑剂、分散剂、助流剂、润湿剂、崩解剂、香料或色料。
5.根据权利要求1所述的应用,其特征在于:所述药物的剂型为口服剂或注射剂。
6.根据权利要求5所述的应用,其特征在于:所述口服剂的形式包括片剂、硬或软胶囊、滴丸、微丸、水性或油混悬剂、乳剂、散剂、颗粒剂、口服液或糖浆剂。
7.根据权利要求5所述的应用,其特征在于:所述注射剂的形式为:灭菌的水性或油性溶液、无菌粉末、脂质体、乳剂或微囊。
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