CN116115760A - Eed抑制剂在制备治疗神经免疫性疾病药物中的应用 - Google Patents
Eed抑制剂在制备治疗神经免疫性疾病药物中的应用 Download PDFInfo
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Abstract
本发明提供EED抑制剂在制备治疗神经免疫性疾病药物中的应用，所述化合物为EED小分子抑制剂，包括式(I)‑(VI)的芳联杂环化合物中的一种或多种。本发明研究证明，无论是敲除EED基因表达或者采用小分子抑制剂来抑制EED蛋白表达都能够抑制树突状细胞激活，进而有效减轻神经系统内炎性浸润和促进损伤髓鞘修复，最终起到治疗神经免疫性疾病的效果。本发明揭示了EED蛋白在免疫细胞及免疫系统中的新角色，为防治神经免疫性疾病提供新的靶点治疗潜在有效药物。式(I)‑(VI)如下：
Description
技术领域
本发明属生物医学和制药领域，涉及抑制EED蛋白活性化合物在制备治疗神经免疫性疾病药物中的应用。
背景技术
神经免疫性疾病是一类免疫过度激活进而攻击神经系统髓鞘的疾病，包括多发性硬化症、视神经脊髓炎谱系疾病、髓鞘少突胶质细胞糖蛋白(MOG)抗体相关疾病、自身免疫性脑炎、重症肌无力和吉兰巴利综合征等(胡学强主编.神经免疫性疾病新进展[M].广州：中山大学出版社,2016.03.)，是青壮年致残的主要原因之一。该类疾病临床主要表现为持续的炎症、疼痛以及认知障碍、运动障碍、共济失调等多功能障碍，病程反复复杂且不可治愈，若不及时治疗会导致残疾甚至死亡。目前，针对神经免疫性疾病的临床常用药物，包括激素类药物、单克隆抗体等，主要用于疾病急性发作期的炎症抑制，在一定程度控制疾病进展，而对于神经髓鞘修复、疾病复发无明显效果，且这些药物均为泛免疫抑制剂，长期应用存在严重的不良反应。因此，临床上亟需特异性神经免疫性疾病的治疗药物。
树突状细胞(Dendritic Cell)作为专职的抗原呈递细胞，在神经免疫性疾病的发生、发展中发挥着至关重要的作用。一方面，树突状细胞是接受病原体刺激的源头细胞之一，被病原体激活后成熟，可释放一系列细胞因子进而塑造体内炎症环境。另一方面，摄取病原体后的成熟树突状细胞还能通过抗原呈递功能激活T、B细胞，触发适应性免疫系统反应。相反，未成熟的树突状细胞则能有效抑制炎症，在神经免疫性疾病的修复过程中发挥着重要的作用。因此，调控树突状细胞是干预神经免疫性疾病的有效策略之一。相较于传统的泛免疫抑制剂，开发抑制树突状细胞激活的药物的有益效果在于，其对于神经免疫性疾病的在治疗效果上更有特异性、针对性，也能降低泛免疫抑制导致的不良反应。
胚胎外胚层发育蛋白EED(Embryonic Ectoderm Development)是组蛋白修饰蛋白，主要功能是促进组蛋白3第27位赖氨酸的三甲基化(H3K27me3)来调控靶基因表达及多类生物学过程，目前报道EED蛋白在肿瘤发生发展、心脏发育、骨骼肌成熟中发挥重要作用。化合物EED226、A-395、MAK-683、FTX-6058、EEDi-5285、EEDi-5273等均为已报道的EED蛋白抑制剂，其作用机制是通过结合EED蛋白来抑制H3K27me3，进而调控下游靶基因表达及生物学功能，目前已明确在肿瘤、遗传性血红蛋白疾病、肾损伤中具有一定的治疗作用，目前尚未有报道EED蛋白抑制剂对于神经免疫性疾病的治疗作用。
发明内容
本发明的目的是提供EED抑制剂在制备治疗神经免疫性疾病药物中的应用，是一种靶向抑制EED蛋白活性的化合物在制备治疗神经免疫性疾病药物中的应用，所述靶向抑制EED蛋白活性的化合物为EED226、A-395、MAK-683、FTX-6058、EEDi-5285、EEDi-5273(式I–式VI所示的芳联杂环化合物)中的一种或多种。
所述药物可以由靶向抑制EED蛋白活性的化合物与药学上可接受的辅料制成，制剂形式为凝胶剂、软胶囊剂、口服制剂、注射液、冻干粉针剂或大输液剂型。
所述靶向抑制EED蛋白活性的化合物可进一步优选为式(I)、(II)、(III)的芳联杂环化合物。
所述神经免疫性疾病可优选为树突状细胞异常激活导致的神经免疫性疾病，包括多发性硬化症、视神经脊髓炎谱系疾病、髓鞘少突胶质细胞糖蛋白抗体相关疾病、自身免疫性脑炎、重症肌无力和吉兰巴利综合征中的一种或多种。所述的神经免疫性疾病可进一步优选为树突状细胞异常激活导致的多发性硬化症、视神经脊髓炎、髓鞘少突胶质细胞糖蛋白抗体相关疾病中的一种或多种。
现有的神经免疫性疾病的临床常用药物包括激素类药物、单克隆抗体等，主要针对效应T、B细胞进行干预，用于疾病急性发作期的炎症抑制，而对于神经髓鞘修复、疾病复发无明显效果，且这些药物均为泛免疫抑制剂，长期应用存在严重的不良反应。本发明与现有技术的区别在于，本发明提供了的用于制备治疗神经免疫性疾病药物的芳联杂环类化合物的作用机制为抑制树突状细胞激活、炎性因子分泌，进而起到促进髓鞘修复和缓解神经免疫性疾病症状的作用，相较于传统泛免疫抑制剂在神经免疫性疾病治疗效果上更有特异性、针对性，也能降低泛免疫抑制导致的不良反应，为治疗神经免疫性疾病提供了新的策略。
文献表明EED226、A-395、MAK-683、FTX-6058、EEDi-5285、EEDi-5273均为EED蛋白抑制剂，能够结合EED蛋白的甲基化结合口袋，诱导其构象变化，进而抑制H3K27me3来调控靶基因表达和生物学活性。本发明申请通过体外实验证实，敲除EED蛋白能抑制树突状细胞的成熟和炎性因子分泌，提示靶向抑制EED蛋白可抑制树突状细胞的免疫激活。进一步选用EED蛋白抑制剂EED226、A-395、MAK-683也能阻断树突状细胞的成熟和炎性细胞因子分泌，表明EED蛋白抑制剂具有抑制树突状细胞免疫激活的作用。进一步优选EED蛋白抑制剂EED226开展自身免疫性脑脊髓炎(Experimental Autoimmune Encephalomyelitis，EAE)动物模型实验证实，这类化合物具有缓解EAE症状的保护作用。本发明专利提供的用于制备治疗神经免疫性疾病药物的芳联杂环化合物的技术方案的实质可能来源于这一类化合物对于EED蛋白的抑制作用。
附图说明
图1是本发明通过细胞实验发现特异性敲除EED蛋白可显著抑制树突状细胞成熟及炎性因子分泌。
图2是本发明通过细胞实验发现EED蛋白抑制剂EED226、A-395、MAK-683可明显抑制树突状细胞成熟及炎性因子分泌。
图3是本发明通过将树突状细胞特异性敲除EED的转基因小鼠构建EAE模型，发现EED敲除可显著缓解多发性硬化症小鼠的临床症状，促进髓鞘修复，抑制树突状细胞成熟和T细胞激活和分化。
图4是本发明体内给予EED抑制剂EED226可显著抑制多发性硬化症小鼠模型中的树突状细胞成熟，阻断T细胞激活和分化，降低临床症状评分，并促进多发性硬化症小鼠模型中的髓鞘修复。
具体实施方式
下面结合附图和实施例对本发明作进一步详细的说明。以下实施例仅用于说明本发明而不用于限制本发明的范围。以下实施例中所用材料、试剂、仪器和方法，通常按照常规条件或按照制造厂商所建议的条件，未经特殊说明，均可通过商业渠道获得。统计学分析采用Graph Pad Prism 8.0.1软件，数据以X±SD表示，t-tests检验用于分析两组间的差异，One-way ANOVA用于多组别数据的方差分析。*，P<0.05；**，P<0.01；***，P<0.001。
实施例1：
提取树突状细胞特异性敲除Eed的转基因小鼠(Eed cKO)和野生型小鼠的骨髓原代树突状细胞(BMDC)，培养6天后采用LPS刺激8小时诱导成熟。Western blot考察EED、H2K27me3的表达水平；qRT-PCR检测Cd40、H2-Aa、H2-d1等树突状细胞成熟指标及促炎因子Il-1β、Ifnγ和抑炎因子Il-10的mRNA水平；流式细胞术共染CD11c和CD80、CD86考察BMDC成熟情况。图1结果显示，敲除Eed的BMDC低表达EED、H3K27me3(图1A)；敲除Eed显著抑制Cd40、H2-Aa、H2-d1表达(图1B)，并抑制Il-1β、促进Il-10表达(图1C)；此外，敲除Eed后成熟BMDC即CD11c+CD80+、CD11c+CD86+细胞比例明显降低(图1D)。
实施例2：
提取野生型小鼠BMDC，培养6天后给予小分子抑制剂EED226、A-395或MAK-683作用24小时，并采用LPS刺激8小时诱导BMDC成熟。Western blot考察EED、H2K27me3的蛋白表达水平；qRT-PCR检测树突状细胞成熟指标、促炎因子的mRNA水平。图2结果显示，EED226、A-395及MAK-683有效抑制BMDC中的H3K27me3表达(图2A)，并显著抑制树突状细胞成熟及炎性水平(图2B)。
实施例3：
采用6-8周龄雌性野生型和Eed cKO小鼠构建EAE模型。具体方法如下：将含4mg/mL髓鞘少突胶质细胞糖蛋白肽(MOG35-55)的磷酸盐平衡生理盐水PBS与含10mg/mL结核分枝杆菌H37Ra的完全弗氏佐剂等体积混合并制备成乳剂，于小鼠背部皮下三点注射200μL乳剂，在免疫当天及2天后分别通过尾静脉注射百日咳毒素稀释液(200ng/只/次)。每天根据临床疾病活动度评分规则对小鼠评分：0分，无任何症状；0.5分，尾巴疲软无力；1分，尾巴完全拖尾；1.5分，一只后脚掌无张力；2分，双后脚掌无张力；2.5分，一只后肢瘫痪或双后肢半瘫；3分，双后肢瘫痪；3.5分，前肢瘫痪或躯干瘫痪；4分，濒死或死亡。图3A结果显示，与野生型小鼠相比，Eed cKO小鼠的临床疾病活动度评分明显降低。
于疾病高峰期(免疫后第22天)麻醉小鼠，经心脏灌注固定后取脊髓腰椎膨大处，组织样本进行冰冻包埋及切片，采用劳克坚牢蓝(Luxol Fast Blue，LFB)染色观察脱髓鞘程度。图3B结果显示，与对照组比较，Eed cKO小鼠脊髓的脱髓鞘损伤情况显著减轻。
于疾病高峰期(免疫后第22天)麻醉小鼠，取出引流淋巴结，充分研磨后离心、裂解红细胞获得单细胞悬液。流式细胞术共染CD11c和CD80或CD86检测树突状细胞成熟情况，共染CD4和IFN-γ或IL-17考察Th1或Th17炎性T细胞分化情况。图3结果显示，特异性敲除Eed显著抑制CD11c+CD80+、CD11c+CD86+的成熟树突状细胞比例(图3C)，并明显抑制CD4+IFN-γ+Th1及CD4+IL-17+Th17炎性细胞分化(图3D)。
实施例4：
采用6-8周龄雌性野生型小鼠构建EAE模型，于第7天开始灌胃给予溶剂对照或EED226(40mg/kg，一天两次)，每天对小鼠进行评分。图4A结果显示，与对照组相比，EED226给药有效降低EAE小鼠的临床疾病活动度。
疾病高峰期收取小鼠脊髓并进行组织病理染色，收取引流淋巴结并进行流式细胞术检测。苏木素-伊红(Hematoxylin-eosin，H&E)及LFB染色结果显示，与对照组比较，EED226给药减轻脊髓中的炎性细胞浸润及脱髓鞘损伤情况(图4B)。流式细胞术结果显示，与对照组比较，EED226给药显著抑制树突状细胞成熟(图4C)及T细胞炎性激活(图4D)。
Claims (5)
1.EED抑制剂在制备治疗神经免疫性疾病药物中的应用，其特征在于，所述化合物是靶向抑制EED蛋白活性的化合物，所述化合物为式(I)-(VI)的芳联杂环化合物中的一种或多种，
2.根据权利要求1所述的应用，其特征在于，所述抑制EED蛋白活性的化合物为式(I)、(II)、(III)的芳联杂环化合物。
3.根据权利要求1所述的应用，其特征在于，所述神经免疫性疾病是指树突状细胞异常激活导致的神经免疫性疾病。
4.根据权利要求3所述的应用，其特征在于，所述的神经免疫性疾病为树突状细胞异常激活导致的多发性硬化症、视神经脊髓炎谱系疾病、髓鞘少突胶质细胞糖蛋白抗体相关疾病、自身免疫性脑炎、重症肌无力和吉兰巴利综合征中的一种或多种。
5.根据权利要求4所述的应用，其特征在于，所述的神经免疫性疾病为树突状细胞异常激活导致的多发性硬化症、视神经脊髓炎、髓鞘少突胶质细胞糖蛋白抗体相关疾病中的一种或多种。
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