CN115381800B - 一种肝x受体的选择性激动剂及应用 - Google Patents
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Abstract
本发明属于化学与医药技术领域，公开了一种肝X受体的选择性激动剂及应用，Petrosiol E作为肝X受体(Liver X Receptors,LXR)的一种选择性激动剂，能够作用于LXRα及LXRβ的配体结合区，剂量依赖地激活LXRα及LXRβ的转录活性，且选择性调控LXRα及LXRβ下游靶基因的表达，有效避免了非选择性LXR激动剂引起的脂肪肝、高血脂等副效应。本发明提供的PetrosiolE是一种性质优良的选择性LXR配体，具有治疗改善动脉粥样硬化、高脂血症、阿尔兹海默症等疾病的活性。
Description
技术领域
本发明属于化学与医药技术领域，涉及一种肝X受体的选择性激动剂及应用。
背景技术
肝X受体(Liver X Receptors,LXR)属于核受体超家族，是一种配体依赖的核转录因子，包括LXRα和LXRβ两个亚型，LXRα和LXRβ在机体的多种组织细胞类型中广泛表达。结构上，LXR由N端的配体非依赖的转录激活区AF1、DNA结合区(DNA binding domain,DBD)及C端的配体结合区(ligand binding domain,LBD)、配体依赖的转录激活区AF2构成。LXR是机体细胞内胆固醇代谢的核心调控因子，LXR与多种疾病的发生密切相关，比如动脉粥样硬化、高脂血症、阿尔兹海默症等。
动脉粥样硬化是动脉血管壁脂质沉积引起的慢性炎症疾病，血管壁处巨噬细胞因胆固醇积累转化形成的泡沫细胞是诱发动脉粥样硬化的关键因素之一,而激活巨噬细胞中的LXR能够促进胆固醇外排、抑制炎症反应从而拮抗泡沫细胞形成及动脉粥样硬化发生。一方面，激活LXR显著上调节巨噬细胞胆固醇外排的因子ABCA1,ABCG1的表达，促进巨噬细胞胆固醇外排(Venkateswaran,A.等人.Control of cellular cholesterol efflux by thenuclear oxysterol receptor LXR alpha.Proc.Natl Acad.Sci.USA 97,12097–12102(2000).Kennedy,M.A.等人.ABCG1 has a critical role in mediating cholesterolefflux to HDL and preventing cellular lipid accumulation.Cell Metab.1,121–131(2005).)。另一方面，激活LXR能够显著抑制巨噬细胞的炎症活化，目前的研究发现LXR能够通过多种机制拮抗巨噬细胞的炎症活化，比如通过ABCA1依赖的方式改变胞膜脂筏成分干扰TLR的信号传导(Ayaka Ito等人，LXRs link metabolism to inflammation throughAbca1-dependent regulation of membrane composition and TLR signaling.Elife(2015)：1-23)。
大脑同样是胆固醇代谢活跃器官，作为胆固醇代谢的关键调节因子，LXR在阿尔兹海默病等神经系统退行性疾病的发生发展中同样具有重要调控作用。小胶质细胞作为神经系统的常驻巨噬细胞，在清除受损神经元、斑块及感染方面起重要作用，对阿尔兹海默病的发生发展有重要调控作用。目前研究发现激活小胶质细胞LXR显著抑制诱发阿尔兹海默病的神经炎症、增强小胶质细胞清除β淀粉样蛋白的能力(Noam Zelcer等人.Attenuation ofneuroinflammation and Alzheimer’s disease pathology by liver xreceptors.Proc.Natl Acad.Sci.USA 104,10601–10606(2007).)，改善诱发神经元损伤的小胶质细胞脂代谢紊乱，表明激活小胶质细胞LXR是有效预防和治疗阿尔兹海默病的重要途径(Ling Wang等人.Liver X receptors in the central nervous system:From lipidhomeostasis to neuronal degeneration.Proc.Natl Acad.Sci.USA99,13878-13883(2002).)。
上述的介绍表明激活LXR能够促进巨噬细胞、小胶质细胞的胆固醇外排、抑制巨噬细胞、小胶质细胞的炎症活化，从而改善与此相关的动脉粥样硬化、阿尔兹海默病等疾病的发生发展，因此LXR被认为是治疗上述相关疾病的有效药物靶标。但是随着研究的深入，人们发现激活LXR在治疗相关疾病的同时会诱发一些副效应，比如激活LXR会增强肝脏脂肪酸从头合成基因表达、抑制肝脏细胞低密度脂蛋白受体(LDLR)表达，从而诱发脂肪肝、高血脂的副效应(Zelcer,N.,等人.LXR regulates cholesterol uptake through Idol-dependent ubiquitination of the LDL receptor.Science 325,100–104(2009).Schultz,J.R.等人.Role of LXRs in control of lipogenesis.Genes Dev.14,2831–2838(2000).)。
目前鉴定发现的具有激活LXR效应的配体主要分为两大类，一类为人工合成的配体分子，另一类为生物体内的内源性配体。人工合成配体GW3965和TO901317具有强烈的LXR激活作用，是常用的激活LXR的工具化合物。氧化胆固醇的衍生物、胆固醇合成的中间产物及一些衍生物是LXR的内源性配体。
基于LXR重要的生物学调控功能，靶向LXR开发治疗效果好、副作用小的治疗药物一直是本领域的研究热点、难点。目前靶向LXR的激动剂类药物由于非选择性激活LXR，具有诱发脂肪肝、血脂紊乱等副效应，极大的限制了该类药物的开发。2018年的研究(EvanD.Muse等人.Cell-specific discrimination of desmosterol and desmosterolmimetics confers selective regulation of LXR and SREBP inmacrophages.Proc.Natl Acad.Sci.USA 115,E4680-E4689(2018).)发现内源性配体desmosterol能够细胞类型特异的激活LXR，具体讲就是选择性激活巨噬细胞中LXR及其下游靶基因的表达而不影响肝脏细胞中与副效应相关的LXR靶基因表达，从而避免LXR激活相关的副效应。因此，寻找具有类似选择性LXR激动活性的化合物是一种有效避免副效应、开发安全性更高的靶向LXR药物的研发新策略。
Petrosiol E是一种海洋天然产物，发明人团队于2014年首次成功合成该化合物并获得化合物合成方法的专利授权(ZL201410344864.5)。目前国内外对Petrosiol E生物活性的研究非常有限，仅有的研究发现其具有促进PC12细胞神经元分化的效应。对于在Petrosiol E的作用分子靶标及其调控胆固醇代谢、抑制炎症活化的生物活性目前缺乏针对性的研究，结果尚不清楚，影响了Petrosiol E的功能的进一步应用。
发明内容
本发明旨在提供一种针对LXR靶点的具有潜在治疗作用的药物或药物成分。
本发明是这样能实现的，一种肝X受体的选择性激动剂及应用，所述选择性激动剂为Petrosiol E。
本发明的另一目的在于提供一种肝X受体的选择性LXR配体，所述选择性LXR配体为Petrosiol E。
本发明的另一目的在于提供一种上述的选择性激动剂在治疗或预防调控胆固醇代谢及抑制炎症活化的生物活性的药物中的应用。
本发明的另一目的在于提供一种上述的选择性LXR配体在治疗或预防调控胆固醇代谢及抑制炎症活化的生物活性的药物中的应用。
进一步，所述调控胆固醇代谢及抑制炎症活化的生物活性为阿尔兹海默症。
进一步，所述调控胆固醇代谢及抑制炎症活化的生物活性为动脉粥样硬化。
结合上述的技术方案和解决的技术问题，请从以下几方面分析本发明所要保护的技术方案所具备的优点及积极效果为：
第一、针对上述现有技术存在的技术问题以及解决该问题的难度，紧密结合本发明的所要保护的技术方案以及研发过程中结果和数据等，详细、深刻地分析本发明技术方案如何解决的技术问题，解决问题之后带来的一些具备创造性的技术效果。具体描述如下：
天然产物Petrosiol E剂量依赖的激活核受体LXRα和LXRβ，能够增强巨噬细胞、小胶质细胞LXR靶基因ABCA1,ABCG1的表达，与内源性选择性配体desmosterol促ABCA1,ABCG1表达效应相当；同时能够显著抑制脂多糖LPS引起的巨噬细胞、小胶质细胞炎症活化；与LXR的非选择性激动剂GW3965不同，Petrosiol E不引起人源肝脏细胞中与LXR激活相关的副效应的靶基因表达增加，在外源脂质孵育的条件下Petrosiol E剂量依赖的抑制肝脏细胞的脂质沉积；在动脉粥样硬化和阿尔兹海默病小鼠模型上Petrosiol E表现出良好的治疗效果。
第二，把技术方案看做一个整体或者从产品的角度，本发明所要保护的技术方案具备的技术效果和优点，具体描述如下：
本发明提供的Petrosiol E是一种结构类型新颖的选择性LXR激动剂，选择性调控LXR下游靶基因表达，能够有效改善LXR活性相关的动脉粥样硬化、阿尔兹海默症等疾病的发生发展，同时有效比较避免LXR激活相关的脂肪肝、高脂血症等副效应。
本发明提供的Petrosiol E是一种性质优良的选择性LXR配体，具有治疗改善动脉粥样硬化、阿尔兹海默症等疾病的活性。
附图说明
图1为本发明实施例提供的Petrosiol E促进LXRα/β转录活性图；
图2为本发明实施例提供的Petrosiol E促进THP-1巨噬细胞LXR靶基因ABCA1,ABCG1表达图；
图3为本发明实施例提供的Petrosiol E促进BV-2小胶质细胞LXR靶基因ABCA1,ABCG1表达图；
图4为本发明实施例提供的Petrosiol E抑制THP-1巨噬细胞炎症基因表达图；
图5为本发明实施例提供的Petrosiol E抑制BV-2小胶质细胞炎症基因表达图；
图6为本发明实施例提供的Petrosiol E不影响肝细胞中LXR靶基因表达图；
图7为本发明实施例提供的Petrosiol E对肝细胞脂质沉积的影响图；
图8为本发明实施例提供的Petrosiol E抑制泡沫细胞和动脉粥样硬化脂质斑块形成图；
图9为本发明实施例提供的Petrosiol E改善ApoE-/-小鼠高血脂图；
图10为本发明实施例提供的Petrosiol E改善SAMP8快速老化小鼠的学习、记忆能力图。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白，以下结合实施例，对本发明进行进一步详细说明。应当理解，此处所描述的具体实施例仅仅用以解释本发明，并不用于限定本发明。
本发明实施例的目的是找到一种针对LXR靶点的具有潜在治疗作用的药物或药物成分。经过大量研究，发明人发现天然产物Petrosiol E剂量依赖的激活核受体LXRα和LXRβ；能够增强巨噬细胞、小胶质细胞LXR靶基因ABCA1,ABCG1的表达，与内源性选择性配体desmosterol促ABCA1,ABCG1表达效应相当；同时能够显著抑制脂多糖LPS引起的巨噬细胞、小胶质细胞炎症活化；有意义的是，与非选择性LXR激动剂GW3965不同，Petrosiol E并不引起人源肝脏细胞的脂肪酸合成等副效应相关的靶基因表达增加，在外源脂质孵育的条件下Petrosiol E剂量依赖的抑制肝脏细胞的脂质沉积；在动脉粥样硬化和阿尔兹海默病小鼠模型上Petrosiol E表现出良好的治疗效果。以上结果表明，Petrosiol E是一种性质优良的选择性LXR配体，具有治疗改善动脉粥样硬化、高脂血症、阿尔兹海默症等疾病的活性。
本发明实施例所采用的技术方案是，一种肝X受体的选择性激动剂、配体及应用，Petrosiol E作为肝X受体(Liver X Receptors,LXR)的一种选择性激动剂，结构如下：
所述Petrosiol E能够作用于LXRα及LXRβ的配体结合区，剂量依赖地激活LXRα及LXRβ的转录活性，且通过选择性调控LXRα及LXRβ下游靶基因的表达，有效避免了非选择性LXR激动剂引起的脂肪肝、高血脂等副效应。
所述Petrosiol E被用作治疗或预防调控胆固醇代谢及抑制炎症活化的生物活性的药物及复合药物组成部分。
以下结合试验过程对本发明实施例进行具体的分析说明。
(1)Petrosiol E剂量依赖的激活核受体LXRα和LXRβ转录活性。
如图1所示，通过经典的双荧光素酶报告基因实验，Hek293细胞中转染表达LXR配体结合区的pCMX-Gal4-mLXRα-LBD或pCMX-Gal4-mLXRβ-LBD表达质粒、tk-UAS-4×Luc报告质粒以及pRL-tk内参质粒的Hek293细胞中，给予不同浓度Petrosiol E孵育24h。结果表明，Petrosiol E剂量依赖的促进LXRα、LXRβ的转录活性，表明Petrosiol E能够与LXRα/β配体结合区结合、促进其转录激活。
(2)Petrosiol E增强巨噬细胞、小胶质细胞LXRα/β靶基因ABCA1,ABCG1表达。
如图2所示，人源THP-1单核细胞经过佛波酯(PMA)诱导分化48小时，形成THP-1巨噬细胞。THP-1巨噬细胞给予不同浓度(0.1，1，5，10，20，30μM)Petrosiol E处理12小时，处理结束后提取RNA,检测LXR调控的靶基因ABCA1,ABCG1表达，结果表明Petrosiol E剂量依赖的促进ABCA1,ABCG1基因表达，其效应与内源性配体Desmosterol相当。
如图3所示，小胶质细胞BV-2给予不同浓度(0.1，1，5，10，20，30μM)Petrosiol E处理12小时，处理结束后提取RNA,检测LXR调控的靶基因ABCA1,ABCG1表达，结果表明Petrosiol E剂量依赖的促进ABCA1,ABCG1基因表达，其效应与内源性配体Desmosterol相当。
(3)Petrosiol E抑制巨噬细胞、小胶质细胞中LXR负调控的炎症基因表达。
如图4所示，激活LXR能够显著抑制巨噬细胞的炎症因子表达，THP-1巨噬细胞给予脂多糖LPS刺激的同时给予不同浓度(0.1，1，5，10，20，30μM)Petrosiol E共处理，处理结束后提取RNA,检测炎症相关靶基因表达。结果表明Petrosiol E剂量依赖的抑制巨噬细胞中炎症基因IL-1β和TNFα表达，其效应显著强于Desmosterol及GW3965。
如图5所示，激活LXR能够显著抑制巨噬细胞的炎症因子表达，BV-2小胶质细胞给予脂多糖LPS刺激的同时给予不同浓度(0.1，1，5，10，20，30μM)Petrosiol E共处理，处理结束后提取RNA,检测炎症相关靶基因表达。结果表明Petrosiol E剂量依赖的抑制巨噬细胞中炎症基因IL-1β和TNFα表达，其效应显著强于Desmosterol及GW3965。
(4)Petrosiol E不影响肝细胞中LXR活化相关副效应的靶基因表达
如图6所示，激活肝细胞的LXR会引起脂肪酸合成基因显著增加进而诱发肝脏脂肪变性的副效应。以人源肝细胞L02为模型，给予Petrosiol E，选择性配体Desmosterol及非选择性配体GW3965,结果表明在肝细胞中，Petrosiol E和Desmosterol均不引起LXR靶基因—脂肪酸合酶(FASN)的表达增加，但GW3965处理显著增加FASN表达。
如图7所示，人源肝细胞L02给予不同浓度的Petrosil E及GW3965处理24小时，处理结束后通过脂质的特异染色油红O染色标示细胞的脂质含量，结果表明非选择性激动剂GW3965具有促进脂质积累效应，而Petrosiol E能够剂量依赖的抑制肝细胞的脂质积累。该结果表明Petrosiol E能够有效避免LXR活化诱发的脂肪肝副效应。
(5)Petrosiol E抑制ApoE-/-小鼠动脉粥样硬化斑块的形成及改善高血脂。
如图8所示，雄性ApoE-/-动脉粥样硬化模型小鼠口服灌胃给予20mg/KgPetrosiol E连续处理8周，处理结束后取胸、腹主动脉，进行油红O染色(标示动脉粥样硬化的脂质斑块)，与对照组相比，Petrosiol E处理组的油红染色脂质斑块显著减少，表明Petrosiol E抑制泡沫细胞形成、抑制动脉粥样硬化斑块形成。
如图9所示，雄性ApoE-/-动脉粥样硬化模型小鼠饲以高脂饮食的同时口服灌胃给予20mg/Kg Petrosiol E，连续处理8周后取血清，测定血脂含量。与对照组相比，PetrosiolE处理组血清低密度脂蛋白、总胆固醇含量显著降低，表明Petrosiol E能够有效改善血脂异常。
(6)Petrosiol E改善SAMP8阿尔兹海默症小鼠的学习记忆能力
如图10所示，雄性SAMP8快速老化阿尔兹海默症小鼠给予20mg/Kg Petrosiol E处理10周，处理结束后通过旷场实验(open field test)、新物体识别实验(Objectrecognition test)评价小鼠的学习记忆能力，与对照组相比，Petrosiol E处理组的学习、记忆能力明显改善
以上所述，仅为本发明的具体实施方式，但本发明的保护范围并不局限于此，任何熟悉本技术领域的技术人员在本发明揭露的技术范围内，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，都应涵盖在本发明的保护范围之内。
Claims (1)
1. Petrosiol E在制备治疗或预防动脉粥样硬化和/或高脂血症的药物中的应用。
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