CN117384258A - 一种神经激肽受体2(nk2r)激动剂及其应用 - Google Patents
一种神经激肽受体2(nk2r)激动剂及其应用 Download PDFInfo
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- CN117384258A CN117384258A CN202311320072.XA CN202311320072A CN117384258A CN 117384258 A CN117384258 A CN 117384258A CN 202311320072 A CN202311320072 A CN 202311320072A CN 117384258 A CN117384258 A CN 117384258A
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- Peptides Or Proteins (AREA)
Abstract
本发明涉及生物医药领域,特别涉及一种神经激肽受体2(NK2R)激动剂及其应用。所述多肽的氨基酸序列如SEQ ID NO.1所示,SEQ ID NO.1的第1个氨基酸和第80个氨基酸通过肽键成环。SEQ ID NO.1所示的环肽能进一步通过解压缩技术得到一系列衍生的环肽和线性肽。本发明提供的多肽能激活NK2R受体,可以用于制备治疗NK2R介导的疾病的药物。
Description
技术领域
本发明涉及生物医药领域,特别涉及一种神经激肽受体2(NK2R)激动剂及其应用。
背景技术
神经肽是泛指存在于神经组织并参与神经系统功能作用的内源性活性物质,是一类特殊的信息物质。特点是含量低、活性高、作用广泛而又复杂,在体内调节多种多样的生理功能,如痛觉、睡眠、情绪、学习与记忆乃至神经系统本身的分化和发育都受神经肽的调节。
神经激肽(neurokinin)是分布在哺乳动物中枢和周围神经系统中的一类神经肽,在炎症、疼痛伤害感受、平滑肌收缩、上皮细胞分泌和增殖中起重要作用。神经激肽物质P(SP)、神经激肽A(NKA)和神经激肽B(NKB)共享一个保守的C末端基序(-Phe-X-Gly-Leu-Met-NH 2,X-Phe/Val)。
神经激肽受体分为NK1R,NK2R和NK3R(neurokinin 1receptor,NK1R;neurokinin2receptor,NK2R;neurokinin 3receptor,NK3R)三种亚型。其中NK1R广泛分布于外周和中枢神经系统;NK2R主要分布于胃肠道、呼吸道和泌尿系统的平滑肌中,CNS也有一定分布;NK3R主要表达于CNS和胃肠道。其中,内源性神经肽神经激肽A(neurokinin A,NKA)主要激活神经激肽NK2受体,物质P(substance P,SP)和神经激肽B(NKB)分别偏向性激活神经激肽NK1R和NK3R。上述三种速激肽都能够作为所有神经激肽受体类型的完全激动剂。
NK2R全名神经激肽受体2(Neurokinin receptor 2),又名速激神经肽受体2(Tachykinin neuropeptide receptor 2)。NKA对NK2R的激活与多种生物反应有关,例如肠道运动功能、平滑肌收缩、炎症和哮喘。鉴于NK2R的重要生理功能,长期以来,它一直被认为是多种疾病的有吸引力的治疗靶点,包括哮喘、抑郁症和焦虑症以及肠易激综合征(IBS)。长期以来,NK2R一直被报道为治疗多种疾病的药物靶点,包括哮喘、抑郁症、焦虑症和肠易激综合征(IBS)。但是速激肽家族的所有成员都能激活NK1R、NK2R和NK3R,仅在亲和力和优先程度上有一定区分,因此针对NK2R靶点的多种药物选择性均较差,易出现呕吐、低血压等副作用。
近年来神经激肽受体结构和功能领域又一突破性进展(Structural insightsinto the activation of neurokinin 2receptor by neurokinin A),该成果不仅揭示了内源性神经激肽NKA激活神经激肽受体NK2R的结构特征,还阐述了内源性神经激肽对受体亚型选择性的分子机制。这些神经激肽的研究丰富了学界对神经激肽系统的结构与功能认识,并为治疗哮喘、抑郁症、焦虑症和肠易激综合征(IBS)等疾病的药物开发提供了重要的理论和结构基础。专利CN116745310A和WO2023118263A1中描述了可以特异性激活NK2R的激动型多肽。然而,只有5种NK1R拮抗剂被批准用于人体,尚未开发出针对NK2R的药物。因此,为满足临床治疗的需要,还需进一步研发结构多样和活性较好的NK2R的激动型治疗药物。
发明内容
为解决现有技术中的不足,本发明提供了一种神经激肽受体2(NK2R)激动剂及其应用。
一方面,本发明提供一种多肽或其药学上可接受的盐,其特征在于,所述多肽选自如(1)~(3)任一项所述活性多肽:
(1)氨基酸序列如SEQ ID NO:1所示的多肽;
(2)项(1)中所述多肽中的10~50个连续氨基酸组成的多肽片段或反向多肽片段;
(3)项(1)和/或项(2)中所述多肽经乙酰化、磷酸化、糖基化、琥珀酰化、泛素化修饰中一种或多种的氨基酸序列的多肽。
其中,氨基酸序列如SEQ ID NO.1所示的80环肽为从多肽库中,通过高通量筛选技术,检测多肽对NK2R受体激活作用得到的80环肽。具体序列如表1所示。该环肽的发现包括多肽库溶解及稀释,利用FLIPR高通量实时荧光成像分析筛选方法根据多肽激活CHO-K1/NK2细胞引起的钙流变化从多肽库中筛选。
筛选得到80环肽SEQ ID NO.1后,对该序列进行氨基酸的序列进行分析和拆解工作,能够设计出不同氨基酸序列的线性肽或者环肽。利用上述筛选80环肽同样的筛选方法,进一步筛选得到对NK2R受体具有激活作用的线性肽或者环肽。
表1本发明氨基酸序列
在一些实施方案中,所述多肽为线性肽.
在一些实施方案中,所述多肽为首尾相连的环肽。
在一些实施方案中,所述多肽由SEQ ID NO:1所示的氨基酸序列中的20~50续氨基酸组成的多肽片段。
在一些实施方案中,所述多肽分子是对SEQ ID NO.1进行分析和拆解得到的环状肽或线性肽,具有25~45个氨基酸。
在一些实施方案中,所述多肽由SEQ ID NO:2~SEQ ID NO:17中任一序列所示的氨基酸序列构成的肽段组成,具体序列如表1所示。其中SEQ ID NO:5所示的多肽为首尾相连的环肽。SEQ ID NO:2~SEQ ID NO:17所示的多肽能够激活NK2R受体。
另一方面,本发明提供一种多肽或其药学上可接受的盐,所述多肽是在氨基酸序列为SEQ ID NO:1~SEQ ID NO:17多肽上经过取代、缺失、添加一个或数个氨基酸,且具有与氨基酸序列为SEQ ID NO:1~SEQ ID NO:17有相同或类似功能的多肽。
在一些实施方案中,所述多肽是在氨基酸序列为SEQ ID NO:1~SEQ ID NO:17多肽上经过取代、缺失、添加一个、两个、三个氨基酸,且具有与氨基酸序列为SEQ ID NO:1~SEQ ID NO:17有相同或类似功能的多肽。
在一些实施方案中,所述多肽是在氨基酸序列为SEQ ID NO:1~SEQ ID NO:17多肽上经过取代、缺失、添加一个氨基酸,且具有与氨基酸序列为SEQ ID NO:1~SEQ ID NO:17有相同或类似功能的多肽。
另一方面,本发明提供一种多核苷酸分子,所述多核苷酸分子包含能够编码上述的多肽分子的一个或两个的多核苷酸。
另一方面,本发明提供一种药物组合物,其包含安全有效量范围内的上述的多肽分子或其药学上可接受的盐及和一种或多种药学上可接受的佐剂、赋形剂、载体、缓冲剂和/或稀释剂。
另一方面,本发明提供上述的的多肽分子、多核苷酸分子或药物组合物在制备治疗与NK2R介导的疾病的药物上的应用。
在一些实施方案中,所述药物用于缓解和/或治疗肥胖、功能性排尿障碍、膀胱活动过度和尿或尿道失禁、糖尿病(例如II型糖尿病)和糖尿病相关病症、哮喘、抑郁症、焦虑症、呕吐。
除非本文中另外定义,否则本专利申请中所用的科学及技术术语应具有一般本领域技术人员通常所理解的含义。
本文所用“多肽库”是湖南中晟全肽生化有限公司利用PICT(PeptideInformation Compression Technology)专利技术,该技术利用生物学手段对多肽信息进行压缩,可将多个多肽的信息集成进一个多肽,从而实现以相对较小的库容包含较大的多肽信息量;通过PICT技术构建含有近73000条80个氨基酸的环肽库。其具体构建方法可以参见专利CN201580081102.3和专利CN201780089941.9。本发明所用多肽库比传统化学合成多肽库信息量大得多的多肽化合物氨基酸序列,库内各化合物均为独立生产,均经过质谱鉴定和精确称量,保证了筛检的准确和稳定,避免了传统的噬菌体库等混合化合物库的失真(实际库容远低于理论值)问题。
附图说明
图1为实施例2SEQ ID NO.2~SEQ ID NO.5对NPFFR2受体激活作用的浓度响应曲线;
具体实施例
应理解,在本发明范围中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成优选的技术方案。
实施例1 80环肽的筛选
1.关键试剂:多肽库(自制)、过表达NK2的CHO细胞(Chinese hamster ovarycell,中国仓鼠暖巢细胞)系,简写为CHO-K1/NK2细胞(金斯瑞,M00200)、Calcium5 AssayKit。
2.高通量筛选过程
2.1.CHO-K1/NK2细胞的培养
2.1.1.细胞复苏:从液氮罐中取出细胞,在37℃水浴锅中快速解冻细胞。将细胞移至15mL离心管中,缓慢加入9mL预热的解冻培养基,800转离心5分钟,移除上清培养基。用5mL解冻培养基重悬细胞,转移至T25培养瓶中,放于37℃,5%CO2的培养箱中培养。细胞复苏第二天更换培养液为生长培养基。
2.1.2.细胞传代:当细胞长满培养瓶80-90%,先用DPBS润洗细胞,再用0.25%胰酶消化细胞;收集细胞悬液至离心管中,800转离心5分钟,移除上清培养基;加入6-8mL新鲜生长培养基,重悬细胞,按照1:3-1:10的比例进行传代,放于37℃,5% CO2的培养箱中培养。传代后每2-3天进行换液。
2.1.3.细胞冻存:当细胞长满培养皿80-90%,先用DPBS润洗细胞,再用0.25%胰酶消化细胞;收集细胞悬液至离心管中,800转离心5分钟,移除上清培养基;用冻存培养基重悬细胞,进行细胞计数,将细胞稀释到2-3×106/mL。每个冻存管分装1mL细胞冻存悬液。将分装好细胞的冻存管放入冻存盒中,将冻存盒放入-80℃冰箱过夜保存后,将冻存管转移到液氮罐中。
2.2.CHO-K1/NK2细胞铺板
测试前24小时,将培养瓶中的CHO-K1/NK2细胞经过0.25%胰酶消化处理并悬浮于细胞培养液中,以每孔8000个细胞的密度使用分液仪加至黑色透明底384孔板中培养,每孔25μL,37℃,5% CO2过夜培养。第二天将细胞转移至30℃继续培养3小时。
2.3.Calcium5 assay kit找工作液准备
测试当日,将Calcium5试剂盒中的组分A溶解于钙染料缓冲液(Loading buffer)并加入250mM丙磺舒配制成含有5mM丙磺舒的钙染料溶液。
吸掉培养基后,在细胞培养板中每孔加入50μL钙染料溶液,放置于37℃孵育2-3小时后转移至室温孵育2小时。
2.4.多肽库溶解及稀释
2.4.1.多肽库溶解
2.4.2.将多肽库96孔深孔板放于离心机4000rpm离心2-3分钟。用自动分液仪向96孔深孔板中加入200μL/孔超纯水中。用硅胶盖密封,放置95℃水浴5分钟。注:此时多肽浓度约为:50μM。
2.4.3.溶解后的96深孔板多肽放于离心机4000rpm离心2-3分钟。
2.5.多肽库稀释
将溶解后用工作站转移至384孔板中,用loading buffer稀释至10μM。
2.6.FLIPR检测
细胞加入Calcium 5染料2小时后,将细胞培养板取出并避光放置于室温10分钟,然后和多肽溶液板一起放入FLIPR仪器,进行检测。设置Galanin(1-30)为激动剂阳性对照,以M35为抑制剂阳性对照。
3.80环肽的确认
3.1.按照步骤2的过程对初筛到的多肽进行确认。
3.2.按照步骤2的过程检测活性多肽的EC50值
检测当天,将将活性多肽母液用1×Loading buffer(含20mMHEPES)(pH:7.4)稀释到50μM(5×浓度),再以3倍稀释8-10个梯度,每个浓度做复孔,测试活性多肽的EC50值。
4.实验结果
通过高通量筛选,从近7.3万条80环肽中找到1条能够在细胞水平激活NK2受体的多肽,即SEQ ID NO.1。
后测试SEQ ID NO.1对NK2受体激活作用的浓度响应曲线,实验结果如表2所示,SEQ ID No.1对NK2受体激活作用的EC50值为1μM。
表2 80环肽SEQ ID NO.1的浓度响应结果
SEQ ID NO. | EC50(μM) |
1 | 1.0 |
实施例2衍生肽的筛选
1.SEQ ID NO.1衍生多肽筛选及确认
应用内部的解压缩技术,对80环肽(SEQ ID NO.1)进行氨基酸的解压缩,设计出不同氨基酸序列的环肽或者线性肽。
按照实施例1中步骤2筛选过程进行筛选,并根据实施例1中步骤3.2对筛选到的解压缩活性多肽进行EC50验证。
2.实验结果
解压缩筛选获得16条就有激动活性的多肽:SEQ ID NO.2~SEQ ID NO.17。测试其分别对NK2受体激活作用的浓度响应曲线,实验结果如图1、表3所示。本发明多肽能够激活NK2受体。
表3 SEQ ID NO.2~17的浓度响应结果
实施例3多肽固相合成
本发明提供的多肽化合物及其衍生物可采用固相合成的方法合成。合成载体为2-Chlotrityl Resin树脂,合成过程中,首先将2-Chlotrityl Resin树脂在N,N-二甲基甲酰胺(DMF)中充分溶胀,然后该固相载体与活化后氨基酸衍生物重复缩合→洗涤→去保护Fmoc→洗涤→下一轮氨基酸缩合的操作以达到所要合成的多肽链长度,最后用三氟乙酸:水:三异丙基硅烷:苯甲硫醚(90:2.5:2.5:5,v:v:v:v)的混合溶液与树脂反应将多肽从固相载体上裂解下来,再由冷冻甲基叔丁基醚沉降后得到直链前体的固体粗品。固体粗品或者氧化后多肽粗品在0.1%三氟乙酸的乙腈/水的体系由C18反相制备色谱柱纯化分离后得到多肽及其衍生物的纯品。
实验试剂
SEQ ID NO:3所示多肽固相合成
SEQ ID NO:3的肽链为GRLFNTGRQRGMKVSLLMKAWRYFWRRQSS。
步骤1:偶联第一位氨基酸Fmoc-Ser(tBu)-OH
将168mg(0.2mmol)2-Chlorotrityl chloride树脂在DCM中充分溶胀1h。称取Fmoc-Ser(tBu)-OH(0.16mmol)和二异丙基乙胺(DIEA,0.64mmol)溶于8mL DCM中并加入树脂中,在室温反应2h。反应完成后加入封闭液(10mL)DCM:甲醇:DIEA(85:10:5,v:v:v)室温10min进行封闭。封闭后的树脂用DCM洗5次,DMF洗5次。
步骤2:直链肽链合成
将步骤1中得到的树脂在DMF中充分溶胀1h。之后将依照的直链前体序列从羧基端第二位氨基酸到氨基端的顺序合成。每一个偶联周期进行如下:
·20%哌啶/DMF(20%v/v,10mL)进行Fmoc-去保护两次,每次8min。
·DMF冲洗树脂6-8次直到中性pH。
·用DMF溶解0.5mmol Fmoc-AA,0.5mmol 6-氯苯并三氮唑-1,1,3,3-四甲基脲六氟磷酸酯(HCTU)和1mmol 4-甲基吗啉(NMM),加入树脂室温反应1h。
·下一个氨基酸偶联之前用DMF冲洗树脂4-6次。
直链多肽合成后用DMF冲洗树脂5次,DCM冲洗树脂5次。树脂在真空中抽干。
步骤3:直链前体肽链切割
将新鲜配制的切割鸡尾酒(10mL)三氟乙酸:水:三异丙基硅烷:苯甲硫醚(90:2.5:2.5:5:,v:v:v:v)加入到步骤1所得树脂中,在室温下振荡反应2小时。反应结束后将反应溶液过滤,并用三氟乙酸洗涤树脂,与反应溶液合并,用4倍体积冷MTBE沉淀得到粗品。用MTBE洗涤粗品3次,放入真空中抽干。
步骤4:多肽的纯化制备
经过0.45um膜过滤后用反相高效液相色谱系统进行分离,缓冲液为A(0.1%三氟乙酸,水溶液)和B(0.1%三氟乙酸,乙腈)。收集产物相关馏分,HPLC鉴定纯度后将>95%的馏分合并,冻干,获得多肽纯品。
步骤5:检测与表征方法
将步骤4的多肽纯品通过分析性高效液相色谱和液相色谱/质谱联用确定纯度及化合物。
本发明其余多肽均可参照上述的Fmoc固相合成方法制备。
应当指出,以上所述仅是本发明的优选实施方式,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
Claims (10)
1.一种多肽或其药学上可接受的盐,其特征在于,所述多肽选自如(1)~(3)任一项所述活性多肽:
(1)氨基酸序列如SEQ ID NO:1所示的多肽;
(2)项(1)中所述多肽中的10~50个连续氨基酸组成的多肽片段或反向多肽片段;
(3)项(1)和/或项(2)中所述多肽经乙酰化、磷酸化、糖基化、琥珀酰化、泛素化修饰中一种或多种的氨基酸序列的多肽。
2.根据权利要求1所述的多肽或其药学上可接受的盐,其特征在于,所述多肽为线性肽或首尾相连的环肽。
3.根据权利要求1所述的多肽或其药学上可接受的盐,其特征在于,所述多肽由SEQ IDNO:1所示的氨基酸序列中的20~50个连续氨基酸组成的多肽片段。
4.根据权利要求1所述的多肽或其药学上可接受的盐,其特征在于,所述多肽由SEQ IDNO:1所示的氨基酸序列中的25~45个连续氨基酸组成的多肽片段。
5.根据权利要求1~4任一项所述的多肽或其药学上可接受的盐,其特征在于,其由SEQID NO:2~SEQ ID NO:17中任一序列所示的氨基酸序列构成的肽段组成。
6.一种多肽或其药学上可接受的盐,其特征在于,所述多肽是在氨基酸序列为SEQ IDNO:1~SEQ ID NO:17的多肽上经过取代、缺失、添加一个或数个氨基酸且与氨基酸序列SEQID NO:1~SEQ ID NO:17具有相同或类似功能的多肽。
7.一种多核苷酸分子,所述多核苷酸分子包含能够编码权利要求1~6任意一项所述的多肽分子的一个或两个的多核苷酸。
8.一种药物组合物,其包含安全有效量范围内的权利要求1~6任意一项所述的多肽分子或其药学上可接受的盐及一种或多种药学上可接受的佐剂、赋形剂、载体、缓冲剂和/或稀释剂。
9.权利要求1~6任意一项所述的多肽分子、权利要求7所述的多核苷酸分子或权利要求8所述的药物组合物在制备治疗与NK2R介导的疾病的药物上的应用。
10.根据权利要求9所述的应用,其特征在于,所述药物用于缓解和/或治疗肥胖、功能性排尿障碍、膀胱活动过度和尿或尿道失禁、糖尿病(例如II型糖尿病)和糖尿病相关病症、哮喘、抑郁症、焦虑症、呕吐。
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