CN115006535A - CBP/p300乙酰化酶抑制剂在制备代谢性疾病药物中的应用 - Google Patents
CBP/p300乙酰化酶抑制剂在制备代谢性疾病药物中的应用 Download PDFInfo
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Abstract
本发明涉及一种CBP/p300乙酰化酶抑制剂在制备代谢性疾病药物中的应用。本发明CBP/p300乙酰化酶抑制剂可以降低体重和脂肪含量，改善糖代谢，不仅抑制白色脂肪组织和肝脏的脂质合成，还能显著降低肝脏糖异生水平，综上CBP/p300HAT的特异性抑制有望成为治疗2型糖尿病、肥胖、非酒精性脂肪肝等代谢性疾病的新靶点。
Description
技术领域
本发明属于代谢性疾病药物领域，特别涉及一种CBP/p300乙酰化酶抑制剂在制备代谢性疾病药物中的应用。
背景技术
蛋白质的翻译后修饰是生命体普遍存在的细胞调控机制，能够赋予修饰蛋白质新的功能特性。随着蛋白质组学和质谱技术的发展，除了组蛋白之外，陆续有细胞核外的非组蛋白乙酰化修饰被发现，几乎涵盖了细胞内各个结构。研究发现蛋白乙酰化可作为桥梁，将生理病理过程中细胞外的营养能量状态与细胞内的代谢通路情况有机联系起来。因此，乙酰化修饰凭借其在治疗代谢性疾病方面展现出的巨大潜力，激发了研究者在该领域开展相关药物研发工作的极大热情。但是过往研究主要集中在去乙酰化酶(HDAC)对能量代谢的调控作用，而乙酰基转移酶(HAT)在代谢过程中的作用则尚不清楚。
CREB结合蛋白(CBP)和与其高度同源的p300蛋白是HAT家族的主要成员，CBP/p300不仅能通过乙酰化组蛋白重塑染色质，以改变其结构和功能，还能通过乙酰化非组蛋白，以调节靶蛋白活性。在CBP/p300敲除小鼠上观察到的胚胎早期致死现象，提示CBP/p300在正常发育过程中发挥重要作用。CBP/p300蛋白分为结构化与非结构化的区域，其中结构化区域包括NRID、CH1(TAZ1)、KIX、BRD、PHD、HAT、ZZ、TAZ2和NCBD。CBP/p300正是通过这些结构域与靶向调节因子的相互作用，从而呈现功能的多样性。HAT结构域作为赖氨酸乙酰化“writer”起到乙酰化靶蛋白的作用。尽管已有研究报道了KIX结构域和CH1结构域参与调控机体能量代谢，但CBP/p300的HAT结构域是否在维持代谢稳态中发挥作用仍不清楚。
常规使用的几种CBP/p300HAT结构域抑制剂虽然被广泛应用于表观遗传学，但它们在体外实验中仅显示出有限的抑制效力，并且选择特异性和细胞渗透性都较差。最新发现的A-485是一亲和力达纳摩尔级别的、高选择性的、类药性的、可口服的CBP/p300HAT小分子抑制剂，细胞渗透性较先前的抑制剂高出至少1000倍。进一步的研究通过分析A-485对124种不同癌症细胞系增殖的影响，发现其在套细胞淋巴瘤、多发性骨髓瘤、非霍奇金淋巴瘤细胞以及AR阳性的前列腺癌细胞中具有显著的活性抑制作用。虽然A-485已显示出显著的抗肿瘤效应，但其代谢作用尚不清楚。
发明内容
本发明所要解决的技术问题是提供一种CBP/p300乙酰化酶抑制剂在制备代谢性疾病药物中的应用，本发明CBP/p300乙酰化酶抑制剂可以降低体重和脂肪含量，改善糖代谢，不仅抑制白色脂肪组织和肝脏的脂质合成，还能显著降低肝脏糖异生水平，综上CBP/p300HAT的特异性抑制有望成为治疗2型糖尿病、肥胖、非酒精性脂肪肝等代谢性疾病的新靶点。
本发明提供一种CBP/p300乙酰化酶抑制剂在制备代谢性疾病药物中的应用。
优选地，所述CBP/p300乙酰化酶抑制剂为A-485。
优选地，所述代谢性疾病包括2型糖尿病、肥胖或非酒精性脂肪肝。
优选地，所述CBP/p300乙酰化酶抑制剂配以药学上可接受的辅料或辅助性成分制备成制剂使用。
优选地，所述制剂选自片剂、粉剂、颗粒剂、胶囊、口服液、缓释剂中的一种。
有益效果
本发明CBP/p300乙酰化酶抑制剂可以降低体重和脂肪含量，改善糖代谢。
本发明CBP/p300乙酰化酶抑制剂不仅抑制白色脂肪组织和肝脏的脂质合成，还能显著降低肝脏糖异生水平。
综上，CBP/p300HAT的特异性抑制有望成为治疗2型糖尿病、肥胖、非酒精性脂肪肝等代谢性疾病的新靶点。
附图说明
图1为A-485降低C57BL/6小鼠的体重和体脂含量结果，其中(A)对照组小鼠(Vehicle)和A-485组小鼠的体重；(B)24小时进食量；(C-D)在体瘦体重和脂肪含量；(E)经代谢笼连续监测48小时的RER。
图2为A-485降低肝脏葡萄糖生成结果，其中(A-B)对照组小鼠和A-485组小鼠的血TG和血TC；(C)随机血糖；(D)空腹6小时血糖；(E)空腹16小时血糖；(F)空腹16小时后的血胰岛素；(G)腹腔注射葡萄糖耐量试验的血糖；(H)腹腔注射胰岛素耐量试验的血糖；(I)腹腔注射丙酮酸耐量试验的血糖；(J)肝脏G6Pc的mRNA水平。
图3为A-485对高脂饲料喂养小鼠的代谢调节作用，其中(A)HFD对照组小鼠和HFDA-485组小鼠的体重；(B-C)在体瘦体重和脂肪含量；(D)16小时空腹血糖；(E)随机血糖；(F)腹腔注射葡萄糖耐量试验的血糖；(G)腹腔注射丙酮酸耐量试验的血糖；(H)肝脏G6Pc的mRNA表达丰度。
图4为A-485抑制白色脂肪组织的脂质合成相关基因的表达结果，其中(A)正常饲料(NCD)喂养条件下，对照组小鼠和A-485组小鼠的eWAT重量；(B)高脂饲料(HFD)喂养条件下，对照组小鼠和A-485组小鼠的iWAT和eWAT的重量；(C)HE染色eWAT和iWAT石蜡切片，标尺＝100μm；(D)eWAT和iWAT的整体形态照片；(E)NCD小鼠eWAT的脂质合成相关基因的表达情况；(F-G)HFD小鼠eWAT和iWAT的脂质合成相关基因的表达情况；(H)NCD小鼠eWAT的FAS和ACC的蛋白表达水平；(I)NCD小鼠eWAT的脂肪酸氧化相关基因的表达情况；(J)NCD小鼠eWAT的UCP1mRNA水平。
图5为A-485抑制脂肪细胞标志基因和关键转录因子的表达结果，(A)正常饲料(NCD)喂养小鼠eWAT的脂肪细胞标志基因的mRNA水平；(B-C)高脂饲料(HFD)喂养小鼠eWAT和iWAT的脂肪细胞标志基因的mRNA水平；(D)PPARγ和C/EBPα在NCD小鼠eWAT中的mRNA水平；(E-F)PPARγ和C/EBPα在HFD小鼠eWAT和iWAT中的mRNA水平；(G)NCD小鼠eWAT的PPARγ和C/EBPα的蛋白表达情况。
图6为A-485抑制原代脂肪细胞的脂质合成相关基因的表达结果，其中，A-485处理24h(A)脂质合成相关基因的mRNA表达情况；(B)FAS和ACC的蛋白表达水平；(C)脂肪细胞标志基因的mRNA表达情况；(D)PPARγ和C/EBPα的mRNA表达水平；(E)PPARγ和C/EBPα的蛋白表达水平。
图7为A-485抑制肝脏脂质合成结果，其中(A)正常饲料(NCD)小鼠肝脏切片的油红染色，标尺＝100μm；(B-C)NCD和高脂饲料(HFD)喂养条件下，肝脏甘油三酯含量；(D-E)正常饲料和高脂饲料喂养条件下，肝脏胆固醇含量；(F)NCD小鼠肝脏的FAS和ChREBP的蛋白表达情况；(G)NCD小鼠肝脏的脂肪酸氧化相关基因的mRNA水平；(H-J)经3μM的A-485处理18小时后，小鼠肝原代细胞脂质代谢相关基因在基础状态和高糖高胰岛素状态下的表达情况。
图8为A-485抑制小鼠肝原代细胞的糖异生结果，其中，小鼠肝原代细胞经A-485和cAMP处理后(A)收集培养基上清以检测内源性葡萄糖生成量，(B-D)糖异生关键基因的mRNA表达情况，(E-F)检测PEPCK的蛋白表达水平；以A-485和二甲双胍(Met)联合处理小鼠肝原代细胞后，(G)检测内源性葡萄糖生成量，(H-J)检测糖异生关键基因的mRNA表达水平。
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。
实施例1
给予正常饲料喂养的8周龄小鼠为期1周的A-485腹腔注射给药(20mg·kg-1·day-1)，以此来探究CBP/p300乙酰化酶活性在在体环境下对能量代谢的影响。A-485给药三天后，A-485组小鼠的体重已显著低于对照组小鼠(图1A)，但两者的进食量并没有差异(图1B)。活体机体成分分析结果提示A-485组小鼠的瘦体重(lean mass)与对照组相比没有显著性差异(图1C)，但体脂含量(fat mass)较对照小鼠组减少14％(图1D)。将两组小鼠放入代谢笼，监测48小时后发现，与对照组小鼠相比，A-485组小鼠的呼吸交换率(RER)并没有发生明显变化(图1E)。这些数据表明，A-485造成的体重减轻与小鼠脂肪含量的减少有关。
评估了A-485对C57BL/6小鼠糖脂代谢的影响。对照组小鼠和A-485组小鼠的血甘油三酯和血胆固醇水平均没有明显差异(图2A-2B)。虽然A-485组小鼠的随机血糖和6小时空腹血糖与对照组相比没有显著性差异(图2C-2D)，但是当空腹时间延长到16小时时，A-485组小鼠的血糖明显低于对照组小鼠(图2E)，空腹16小时后的血胰岛素水平则与对照组相当(图2F)。腹腔内葡萄糖耐量试验(IPGTT)：禁食16小时后，检测其空腹血糖(即0分钟)，给予这两组小鼠葡萄糖以2g/kg体重的剂量腹腔注射，依次检测注射葡萄糖后的15、30、60和120分钟的血糖，结果显示，A-485组小鼠在0、15和30分钟这三个时间点上的血糖水平略低于对照组(图2G)。胰岛素耐量试验(IPITT)：禁食6小时后，检测其空腹血糖(即0分钟)，随后将优泌林R胰岛素以0.75UI/kg体重的剂量予以小鼠腹腔注射，依次检测注射胰岛素后的15、30、60和120分钟的血糖。结果则提示两组小鼠的胰岛素敏感性没有差异(图2H)。腹腔内丙酮酸耐量试验(IPPTT)：小鼠过夜禁食16小时后，检测其空腹血糖(即0分钟)，随后将丙酮酸钠以2g/kg体重的剂量予以小鼠腹腔注射，依次检测注射丙酮酸钠后的15、30、60和120分钟的血糖，发现A-485组小鼠各个时间点的血糖水平均明显低于对照组，15分钟和30分钟的差异尤为显著(图2I)。G6Pc作为糖异生关键酶，其mRNA在A-485组小鼠肝脏上的表达丰度明显低于对照组小鼠(图2J)。这些结果提示A-485引起的血糖变化可能与其对肝糖生成的抑制作用有关。
C57BL/6小鼠从5周龄起给予60％脂肪热能的高脂饲料喂养14周，对高脂饲料喂养(HFD)的C57BL/6小鼠同样给予了为期1周的A-485腹腔注射(20mg·kg-1·day-1)，并检测了相关代谢表型。给药3天后，与在正常饲料喂养(NCD)小鼠上的发现类似，A-485也导致高脂饲料喂养小鼠体重减轻，瘦体重与对照组小鼠没有显著性差异，而体脂含量明显减少(图3A-3C)。相较于HFD对照组小鼠，HFD A-485组小鼠空腹血糖更低(图3D)，随机血糖则没有显著差异(图3E)。HFD A-485组小鼠不仅葡萄糖耐量得到了明显改善(图3F)，而且在丙酮酸耐量试验中，它们在各个时间点的血糖水平同样明显低于HFD对照组小鼠(图3G)。此外，HFDA-485组小鼠肝脏的G6Pc mRNA的表达丰度也明显降低(图3H)。
A-485腹腔注射1周后，分离小鼠各组织器官，发现A-485组小鼠的附睾白色脂肪组织(eWAT)重量和腹股沟白色脂肪组织(iWAT)的重量都显著低于对照组小鼠(图4A-4B)，并且A-485组小鼠的脂肪细胞大小和整体组织大小都明显小于对照组小鼠(图4C-4D)。随后进一步地观察了正常饲料和高脂饲料喂养小鼠的eWAT和iWAT的脂质代谢相关基因的表达情况，发现A-485显著降低了脂质合成关键基因(脂肪酸合成酶，FASN；乙酰辅酶A羧化酶，ACC；硬脂酰辅酶A去饱和酶1，SCD1；甘油二酯酰基转移酶2，DGTA2)和相关转录因子(碳水化合物反应元件结合蛋白，ChREBP；固醇调控元件结合蛋白，SREBP-1c)的mRNA表达水平(图4E-4G)。相应的，FAS和ACC的蛋白水平也被A-485显著下调(图4H)。另一方面，对照组小鼠和A-485组小鼠WAT的脂肪酸氧化相关基因(肉毒碱棕榈酰转移酶，CPT1α；乌头酸水合酶，ACO；中链酰基辅酶A脱氢酶，MCAD；极长链酰基辅酶A脱氢酶，ACADVL)的mRNA水平并没有表现出明显差异(图4I)，棕色脂肪组织的标记基因解偶联蛋白1(UCP1)的基因表达水平也没有发生显著变化(图4J)。这些结果表明，A-485主要通过抑制WAT的脂质合成来降低机体脂肪含量。还发现A-485组小鼠WAT的脂肪细胞标志基因(脂肪酸结合蛋白，FABP4；脂蛋白脂解酶，LPL)的表达水平明显低于对照组小鼠(图5A-5C)。过氧化物酶体增殖物激活受体γ(PPARγ)和CCAAT增强子结合蛋白α(C/EBPα)是调控脂肪细胞形成的两个关键转录因子，它们的基因和蛋白表达水平也都受到了A-485的显著抑制(图5D-5G)。
在体外进一步验证了A-485对脂肪细胞的作用。分离正常C57BL/6小鼠的原代前脂肪细胞，体外培养，白色化诱导完成后，给予3μM A-485处理24小时。A-485显著抑制了FAS、ACC等脂质合成相关基因的表达(图6A-6B)。与对照组相比，A-485处理组的脂肪细胞标志基因和关键转录因子(PPARγ和C/EBPα)的表达水平也明显下降(图6C-6E)。综上，推测CBP/p300HAT的乙酰化酶活性对于维持白色脂肪组织正常的脂肪形成必不可少。
正常饲料(NCD)小鼠肝脏切片油红染色显示A-485组小鼠肝脏的脂滴数量明显少于对照组小鼠(图7A)。相应的，无论是正常饲料喂养，还是高脂饲料喂养，A-485组小鼠肝脏的甘油三酯和胆固醇含量均明显低于对照组小鼠(图7B-7E)。A-485腹腔注射给药也显著抑制了FAS和ChREBP的蛋白表达水平(图7F)。但与在WAT上的发现一致的是，A-485并未改变肝脏脂肪酸氧化相关基因的表达水平(图7G)。随后利用小鼠肝原代细胞进一步探究A-485对肝脏脂代谢的影响。如图7H所示，在100nM胰岛素和25mM葡萄糖的刺激条件下，A-485显著下调了脂质合成关键基因(包括FASN、ACC、SCD1和三羟基三甲基辅酶A合成酶1(HMGCS1))的mRNA表达水平。肝原代细胞的FAS、ACC和ChREBP的蛋白水平在经A-485处理后呈显著降低(图7I)。尽管A-485在基础状态下可增加脂肪酸氧化相关基因(例如MCAD、ACO、CPT1α和成纤维细胞生长因子21(FGF21))的表达，但在高糖高胰岛素条件下，这种促进作用会明显减弱(图7J)。上述结果提示A-485主要通过抑制脂质合成来降低肝脏脂滴堆积。
实施例2
小鼠肝原代细胞经3μM A-485和100μM cAMP处理24小时后，收集培养基上清以检测内源性葡萄糖生成量，发现cAMP诱导的内源性葡萄糖生成明显减少(图8A)。磷酸烯醇型丙酮酸羧激酶(PEPCK)、G6Pc和果糖1,6-二磷酸酶(FBP)是糖异生的关键酶，cAMP刺激能显著增加它们的表达水平。当小鼠肝原代细胞经3μM A-485和100μM cAMP处理8小时后，cAMP对这3个糖异生关键酶mRNA的诱导作用即被阻断(图8B-8D)，但此时PEPCK的蛋白水平尚未出现明显变化(图8E)。将A-485和cAMP处理时间延长至16小时后，PEPCK的蛋白水平显著降低(图8F)。以3μM A-485和2mM二甲双胍(Met)联合处理小鼠肝原代细胞24小时后，检测内源性葡萄糖生成量，并以3μM A-485和2mM Met联合处理小鼠肝原代细胞8小时后，检测糖异生关键基因的mRNA表达水平，发现两种药物对内源性葡萄糖的生成和糖异生关键酶的表达均具有协同抑制作用(图8G-8J)。
Claims (5)
1.一种CBP/p300乙酰化酶抑制剂在制备代谢性疾病药物中的应用。
2.根据权利要求1所述的应用，其特征在于，所述CBP/p300乙酰化酶抑制剂为A-485。
3.根据权利要求1所述的应用，其特征在于，所述代谢性疾病包括2型糖尿病、肥胖或非酒精性脂肪肝。
4.根据权利要求1所述的应用，其特征在于，所述CBP/p300乙酰化酶抑制剂配以药学上可接受的辅料或辅助性成分制备成制剂使用。
5.根据权利要求4所述应用，其特征在于，所述制剂选自片剂、粉剂、颗粒剂、胶囊、口服液、缓释剂中的一种。
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| CN116904469A (zh) * | 2023-09-12 | 2023-10-20 | 首都儿科研究所 | 一种p300蛋白表达的抑制剂和制备方法及其用途 |
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| FEIYE ZHOU ETAL.: "Selective inhibition of CBP/p300 HAT by A-485 results in suppression of lipogenesis and hepatic gluconeogenesis" * |
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| CN116904469A (zh) * | 2023-09-12 | 2023-10-20 | 首都儿科研究所 | 一种p300蛋白表达的抑制剂和制备方法及其用途 |
| CN116904469B (zh) * | 2023-09-12 | 2024-01-23 | 首都儿科研究所 | 一种p300蛋白表达的抑制剂和制备方法及其用途 |
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