CN115260292A - 一种新型的镇痛多肽 - Google Patents
一种新型的镇痛多肽 Download PDFInfo
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- CN115260292A CN115260292A CN202211036618.4A CN202211036618A CN115260292A CN 115260292 A CN115260292 A CN 115260292A CN 202211036618 A CN202211036618 A CN 202211036618A CN 115260292 A CN115260292 A CN 115260292A
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- conotoxin
- neuralgia
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- polypeptide
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Abstract
本申请提供了一种、具有明显镇痛效果且活性更好的作用于α9α10nAChR的芋螺毒素的突变体多肽，其所述芋螺毒素的突变体为[S4Dap,S9Dap]；本申请公开的芋螺毒素的突变体多肽用于治疗或缓解神经痛、成瘾、帕金森症、癫痫症、局部缺血、兴奋性神经元细胞死亡、痴呆、乳腺癌、肺癌、脑脊髓炎、癌症与癌症化疗、化疗药物诱导的疼痛、酒精中毒、坐骨神经痛、糖尿病、三叉神经痛、硬化症、带状疱疹痛、内脏疼痛、机械伤和手术伤、艾滋病、头部神经瘫痪、药物中毒、工业污染中毒、淋巴神经痛、骨髓瘤、多点运动神经痛、慢性先天性感觉神经病、急性剧烈自发性神经痛、挤压神经痛、脉管炎、血管炎、局部缺血、尿毒症、儿童胆汁、肝脏疾病、慢性呼吸障碍、复合神经痛、多器官衰竭、脓毒病/脓血症、肝炎、卟啉症、维生素缺乏、慢性肝脏病、原生胆汁硬化、高血脂症、麻疯病、莱姆关节炎、感觉神经束膜炎或过敏症。
Description
技术领域
本发明涉及生物医药领域。具体涉及一种由作用α9α10nAChR芋螺毒素突变体得到的镇痛多肽及其应用。
背景技术
芋螺毒素是由海洋软体动物芋螺(Conus)分泌的一类用于自卫和捕食的活性肽类毒素。芋螺毒素分子质量小，通常由10-30个氨基酸残基组成，大多富含半胱氨酸，具有高度保守的二硫键骨架。芋螺毒素种类繁多，可达10万种以上，其一级结构多变，但信号肽及前导肽序列保守。根据保守的信号肽序列，芋螺毒素可分为：A、M、O、I、P、S、T等超家族(superfamily)，再依据家族中毒素的半胱氨酸骨架，结合其药理活性，又可分为α、μ、ω、δ、Ψ、σ、λ、κ、γ等家族。芋螺毒素能特异性地作用于体内多种(钾、钠、钙等)离子通道、细胞膜上的各种神经递质和激素的受体，从而干扰细胞或神经中的信号传递。因此，在治疗慢性疼痛、急性疼痛、癫痫、神经保护、心血管疾病、精神失常、运动失调、痉挛症、癌症及中风等方面具有广泛的应用前景。如O-超家族中的ω-芋螺毒素可直接作用于钙离子通道，阻断痛觉传递，并具有镇痛效应。由于芋螺毒素在作为分子探针用于神经药理研究及作为新型药物前导物开发临床用新药方面具有极高的研究和利用价值。在芋螺毒素中，ω-MVIIA来源于海洋生物幻芋螺(Conus magus，也称僧袍芋螺)，能特异地阻断钙离子通道，阻止疼痛信号的传导，以其为有效成分的Ziconotide(商品名PrialtTM)已被FDA批准用于治疗慢性疼痛(Terlau,Olivera.Conus venoms:a rich source of novel ionchannel-targetedpeptides. Physiol Rev.2004,84:41-68)。芋螺毒素中的α类芋螺毒素(α-Conotoxins)具有阻断烟碱乙酰胆碱受体(nAChRs)的功能；不含有半胱氨酸的芋螺毒素肽Conantokins则具有阻断N-甲基-D- 天冬氨酸受体(NMDA受体，N-methyl-D-aspartic acid receptor，NMDAR)的功能。
在神经型nAChRs的各种亚型中，α9α10亚型在生物医药领域备受关注。α9α10烟碱型乙酰胆碱受体是由α9和α10两种亚基组成的跨膜五聚体，是一种配体门控离子通道，该受体最早被发现存在于耳蜗毛细胞中，介导橄榄耳蜗胆碱能纤维和传出神经之间的突触传递，后被证明在白细胞、背根神经节、垂体、皮肤角质细胞和精液中也有分布。研究表明，乙酰胆碱受体中的α9α10亚型可能是治疗慢性疼痛，特别是神经性疼痛的潜在靶点(McIntosh,J.M.； Absalom,N.；Chebib,M.；Elgoyhen,A.B.Vincler,M.,Alpha9 nicotinicacetylcholine receptors and thetreatment of pain.Biochemicalpharmacology2009,78(7),693-702.Satkunanathan,N.； Livett,B.；Gayler,K.Sandall,D.；Down,J.；Khalil,Z.,Alpha-conotoxin Vc1.1alleviates neuropathic pain andacceleratesfunctional recovery of injured neurones.Brain research2005,1059(2),149-58.)。α9α10nAChR阻断剂具有治疗神经痛、预防神经受伤、和加速受伤神经恢复的功能，可能是通过免疫机制发挥作用(Holtman,J.R.；Dwoskin,L.P.； Dowell,C.；Wala,E.P.；Zhang,Z.；Crooks,P.A.；McIntosh,J.M.,The novel small moleculealpha9alpha10 nicotinicacetylcholine receptor antagonist 5ZZ-204G isanalgesic.European journal ofpharmacology 2011,670(2-3),500-8.Zheng,G.；Zhang,Z.； Dowell,C.；Wala,E.；Dwoskin,L.P.；Holtman,J.R.；McIntosh,J.M.；Crooks,P.A.,Discovery of non-peptide,smallmolecule antagonists of alpha9alpha10 nicotinic acetylcholinereceptorsas novel analgesics for the treatment of neuropathic andtonic inflammatorypain.Bioorganic&medicinal chemistry letters2011,21(8),2476-9；Romero HK,Christensen SB,Di Cesare Mannelli L,Gajewiak J,Ramachandra R,Elmslie KS,Vetter DE,Ghelardini C,Iadonato SP, Mercado JL,Olivera BM,McIntoshJM.Inhibition ofα9α10nicotinic acetylcholine receptors prevents chemotherapy-induced neuropathic pain.Proc Natl Acad Sci U S A.2017 Mar 7；114(10):E1825-E1832)。此外，α9α10nAChR还与伤口愈合、耳部疾病、肺癌、乳腺癌以及皮肤病等诸多疾病密切相关。角化细胞上的α9α10nAChR在伤口愈合的病理生理学过程中起着很重要的作用(Chernyavsky,A.I.；Arredondo,J.；Vetter,D.E.；Grando,S.A.,Central role of alpha9acetylcholinereceptor in coordinating keratinocyte adhesion and motility attheinitiation of epithelialization.Experimental cell research 2007,313(16),3542-55)。新近研究表明，α9亚基在乳癌组织中过表达，促进乳腺癌的发生 (Chen,C.S.,Lee,C.H.,Hsieh,C.D.,Ho,C.T.,Pan,M.H.,Huang,C.S.,Tu,S.H.,Wang, Y.J.,Chen,L.C.,Chang,Y.J.,Wei,P.L.,Yang,Y.Y.,Wu,C.H.,and Ho,Y.S.(2011) Nicotine-inducedhuman breast cancer cell proliferation attenuated bygarcinol throughdown-regulation of the nicotinicrecep toran dcycl in D3 proteins.Breast cancerresearch and treatment 125,73-87.Lee,C.H.,Huang,C.S., Chen,C.S.,Tu,S.H.,Wang,Y.J.,Chang,Y.J.,Tam,K.W.,Wei,P.L.,Cheng,T.C.,Chu, J.S.,Chen,L.C.,Wu,C.H.,andHo,Y.S.(2010)Overexpression and activation of thealpha9-nicotinic receptorduring tumorigenesis in human breastepithelial cells.Journal of the NationalCancer Institute 102,1322-1335)。α9亚基变体影响支气管细胞的转化与增殖，该亚基在肺癌的治疗中具有非常重要的意义(Chikova,A.；Grand o,S.A.,Naturally occurringvariants of human Alpha 9nicotini crecept or di fferentially affect bronchialcell proliferation andtrans formation.PloS one 2011,6(11),e27978.)。研究表明，α9α10乙酰胆碱受体(nAChR)的拮抗剂在动物疼痛模型中表现出了良好的镇痛效果，其中α-芋螺毒素Vc1.1、RgIA和GeXIVA是目前活性较好的鼠源α9α10nAChR抑制剂，三者在不同动物疼痛模型中均表现出了卓越的镇痛作用，而之前发现的α-芋螺毒素RgIA和Vc1.1，对大鼠α9α10nAChRs的阻断活性很强，尤其在啮齿动物α9α10nAChR上的活性远高于其在人α9α10nAChR上的活性，二者相比下降了300－400倍(Zhangsun D,Zhu X,Kaas Q etal.alphaO-Conotoxin GeXIVA disulfide bond isomers exhibit differentialsensitivity for various nicotinic acetylcholine receptors but retain potencyand selectivity for the human alp ha9alpha10subtype.Neuropharmacology 2017；127:243-252)。
在CN 114573674 A中根据α-芋螺毒素与α9α10nAChR(即α9α10烟碱型乙酰胆碱受体)相互作用的机理，设计多条α-芋螺毒素单体肽突变体。筛选抑制活性高、镇痛效果好的单体肽突变体Gex-2。进一步通过对Gex-2进行丙氨酸扫描、天冬氨酸扫描、精氨酸扫描、精氨酸-瓜氨酸替代、D型氨基酸替换等手段进行突变获得Gex-2的系列衍生物，能够提高 CCI大鼠的痛阈阈值，但是Gex-2活性略有降低，Gex-3活性略高，同时镇痛作用的强度在一定范围内与用药剂量相关；在CN 112010959 A中提供了一种αO-芋螺毒素肽GeXIVA新突变体，其能够特异性地阻断α9α10乙酰胆碱受体，但其序列长、空间结构不稳定、制备成本较高，工作量较大。
芋螺毒素Mr1.1最初发现作用α7nAChR(Peng,C.,Chen,W.,Sanders,T.,Chew,G.,Liu,J., Hawrot,E.and Chi,C.(2010)Chemical synthesis and characterization oftwoα4/7-conotoxins.Acta Biochim.Biophys.Sin.(Shanghai)42:745-753)，Mr1.1能够特异性作用于老鼠α7nAChR，并在体内显示镇痛活性。Mr1.1是α9α10nAChR的特异性抑制剂，其靶向性远高于α7nAChR。 Mr1.1对α9α10nAChR的抑制活性要大于Vc1.1和RgIA，为102.6±6.7nM。同时，研究发现PeIA针对人α9α10nAChR的活性显著优于Vc1.1与RgIA(Clark,R.J.,Fischer,H., Nevin,S.T.,Adams,D.J.and Craik,D.J.(2006)The synthesis,structuralcharacterization,and receptor specificity of the alpha-conotoxin Vc1.1J.Biol.Chem.281:23254-23263；Yu,R.,Tae,H.S., Tabassum,N.,Shi,J.,Jiang,T.andAdams,D.J.(2018)Molecular Determinants Conferring the Stoichiometric-Dependent Activity ofα-Conotoxins at the Humanα9α10Nicotinic AcetylcholineReceptor Subtype J.Med.Chem.61:4628-4634)。
综上，在众多芋螺毒素的研究中，有些作用α9α10nAChR的芋螺毒素不具物种选择性但本身活性比较低，不利于开发应用；同时大量研究表明作用α9α10nAChR的芋螺毒素本身及衍生物大都存在物种选择性，对人源受体活性也普遍偏低；因此，亟需开发新的针对人源受体活性强的镇痛、抗肿瘤多肽类药物。
发明内容
本发明提供一种具有明显镇痛效果且活性更好的多肽，所述多肽是在对α-芋螺毒素的氨基酸突变基础上获得的多肽。基于此，提出如下发明：
第一方面，本发明提供一种作用于α9α10nAChR的芋螺毒素的突变体多肽；所述芋螺毒素的突变体多肽包含第4、第9或第10位点及其相互组合位点的氨基酸突变。进一步的，优选所述芋螺毒素的突变体多肽包含第4位和第9位同时突变。
进一步，所述芋螺毒素的突变体多肽的突变位点是由丝氨酸突变为Dap。
更进一步，所述芋螺毒素的突变体多肽的突变位点是指第4位和第9位同时由丝氨酸突变为Dap。进一步，所述的双突变体为[S4Dap,S9Dap]。
进一步，所述芋螺毒素的突变体多肽是指α-芋螺毒素的突变体多肽，更进一步，所述α-芋螺毒素的突变体多肽选自Mr1.1、PeIA、Vc1.1、RgIA和/或RgIA4及其组合的突变体多肽。
一些实施方式中，当α-芋螺毒素的突变体多肽选自Mr1.1和PeIA的突变体时，所述突变体多肽包含GCC(Dap)HPAC[Dap]VNX1PX2X3C(nh2)所示的氨基酸序列，其中X1选自N或H；X2选自D或E；X3选自L或I；nh2为C端酰胺化。
在另一些实施方式，PeIA突变多肽的序列为:GCC(Dap)HPAC(Dap)VNHPELC(nh2)；Mr1.1突变多肽的序列为:GCC(Dap)HPAC(Dap)VNNPDIC(nh2)；Vc1.1突变多肽的序列为:GCC(Dap)DPRCNYDHPEIC(nh2)；RgIA突变多肽的序列为:GCC(Dap)DPRCRYRCR。
第二方面，提供一种包含本发明芋螺毒素的突变体多肽的组合物，所述组合物可以包含制剂所需的载体或辅料。
第三方面，本发明进一步提供一种包含所述芋螺毒素的突变体多肽的融合蛋白，所述融合蛋白通过linker或连接臂将芋螺毒素的突变体多肽与其它序列连接。
第四方面，本发明提供一种核酸分子，其编码本发明的芋螺毒素的突变体多肽。
第五方面，本发明提供一种构建体，其包含前述的核酸分子。
第六方面，本发明提供一种宿主细胞，其包含前述的核酸分子和/或前述的构建体，和/ 或所述宿主细胞被前述的核酸分子和/或前述的构建体转化或转染。
第七方面，本发明提供一种药物组合物，所述药物组合物包含前述任一项所述的活性多肽、前述融合蛋白、前述核酸分子、前述构建体、前述宿主细胞，以及可选的药学上可接受的辅料。
第八方面，本发明提供前述任一项所述的突变体多肽、前述融合蛋白、前述核酸分子、前述构建体、前述宿主细胞、前述药物组合物抑制α9α10nAChR受体的作用，其中所述α9α10nAChR包括人α9α10nAChR、鼠α9α10nAChR。
进一步，抑制α9α10nAChR受体的作用包括对疾病的治疗。所述疾病包括神经痛、成瘾、帕金森症、癫痫症、局部缺血、兴奋性神经元细胞死亡、痴呆、乳腺癌、肺癌、脑脊髓炎、癌症与癌症化疗、化疗药物诱导痛、酒精中毒、坐骨神经痛、糖尿病诱发痛、三叉神经痛、硬化症、带状疱疹痛、机械伤和手术伤、艾滋病诱发痛、内脏疼痛、头部神经瘫痪、药物中毒、工业污染中毒、淋巴神经痛、骨髓瘤、多点运动神经痛、慢性先天性感觉神经病、急性剧烈自发性神经痛、挤压神经痛、脉管炎、血管炎、局部缺血、尿毒症、儿童胆汁、肝脏疾病、慢性呼吸障碍、复合神经痛、多器官衰竭、脓毒病/脓血症、肝炎、卟啉症、维生素缺乏、慢性肝脏病、原生胆汁硬化、高血脂症、麻疯病、莱姆关节炎、感觉神经束膜炎或过敏症。
本发明的芋螺毒素的突变体多肽在第4、第9、第10位的突变使得活性和镇痛效果得到了提高，尤其是第4位和第9位同时突变后的多肽活性和镇痛效果显著提高。
附图说明
图1Mr1.1单突变位点的筛选。
图2α-芋螺毒素Mr1.1及其类似物对人(h)α9α10nAChRs的抑制作用(平均±SD， n＝6–12)。
图3α-芋螺毒素PeIA单突变体PeIA[S4Dap]对(h)α9α10nAChRs的抑制作用， IC50＝5.3nM(5.0–5.7；95％CI)。
图4α-芋螺毒素PeIA双突变体PeIA[S4Dap,S9Dap]对(h)α9α10nAChRs的抑制作用，IC50＝0.93nM(5.0–5.7；95％CI)。
图5Mr1.1及相关类似物在25μg/kg给药剂量下，单次给药后的痛阈测试。(mean±SEM(n＝8)，*0.01﹤P﹤0.05,**0.001﹤P﹤0.01,***0.0001﹤P﹤0.01,and****0.0001﹤P﹤0.0001)。
具体实施方式
为更好理解本发明，首先定义一些术语。其他定义则贯穿具体实施方式部分而列出。
如本文所用，术语“多肽”意图涵盖单个“多肽”以及多个“多肽”，并且是指由通过酰胺键(还被称为肽键)线性连接的单体(氨基酸)构成的分子。术语“多肽”是指含有两个或更多个氨基酸的任何一个或多个链，并且不是指特定长度的产物。因此，肽、二肽、三肽、寡肽、“蛋白质”、“氨基酸链”或用于表示两个或更多个氨基酸的一个或多个链的任何其它术语都被包括在“多肽”的定义内，并且术语“多肽”可以代替或与任何这些术语互换使用。本发明活性多肽可以是天然多肽(或野生型多肽)、重组多肽或合成多肽。本发明的多肽可以是分离的、化学合成的，或重组的。相应地，本发明多肽可用常规分离提取方法、或可用常规方法人工合成，也可用重组方法生产。优选地，本发明的活性多肽可通过固相Fmoc化学合成。
术语“核酸”是指多核苷酸中存在的任何一种或多种核酸区段，例如DNA或RNA片段。“分离的”核酸或多核苷酸意图为从其原生环境中移出的核酸分子、DNA或RNA。例如，出于本发明的目的，载体中所含有的编码多肽的重组多核苷酸被认为是分离的。分离的多核苷酸的其它实例包括维持在异源宿主细胞中的重组多核苷酸或溶液中的纯化(部分或实质性) 的多核苷酸。分离的RNA分子包括本发明的多核苷酸的体内或体外RNA转录物。根据本发明的分离的多核苷酸或核酸还包括合成产生的所述分子。另外，多核苷酸或核酸可以是或可以包括调控元件，如启动子、核糖体结合位点或转录终止子。
术语“融合蛋白”、术语是指包含除了编码原始或天然全长蛋白或其子序列的氨基酸序列之外的氨基酸、包含代替编码原始或天然全长蛋白或其子序列的氨基酸序列的氨基酸序列、包含少于编码原始或天然全长蛋白或其子序列的氨基酸序列的氨基酸序列和/或包含不同于编码原始或天然全长蛋白或其子序列的氨基酸序列的氨基酸序列的蛋白。
术语“突变”：指生物体、病毒或染色体外DNA基因组核苷酸序列的改变，包括，碱基变化的碱基替换、DNA插入、DNA缺失或DNA重复引起的序列的改变；本发明“芋螺毒素的突变体多肽”的突变是依据作用于α9α10nAChR而设计的序列突变，即指对芋螺毒素在4/9号位Ser同时进行Dap替换，得到双突变体[S4Dap,S9Dap]类似物；其中芋螺毒素选自 Mr1.1、PeIA、Vc1.1、RgIA和/或RgIA4及其组合。
除非另外说明，否则术语“病症”和“疾病”在本文中互换使用。
术语“组合物”或“药物组合物”可包括含有本公开的活性多肽以及例如药学上可接受的载剂、赋形剂或稀释剂的组合物，所述组合物被施用至受试者个体。
术语“药学上可接受的”是指在合理的医学判断范围内适合于与人类和动物的组织接触而无过度毒性或其它并发症、与合理的利益/风险比相称的组合物。在一些方面，本文所述的多肽、多核苷酸、组合物和疫苗是药学上可接受的。
“有效量”是以单剂量或作为一系列剂量的一部分向个体施用对于治疗或预防而言有效的量
术语“受试者”是指需要诊断、预后、免疫或治疗的任何受试者，特别是哺乳动物受试者。哺乳动物受试者包括但不限于人、家养动物、农场动物、动物园动物如熊、运动动物、宠物动物如狗、猫、豚鼠、兔、大鼠、小鼠、马、牛、熊、奶牛；灵长类动物，如猿、猴、猩猩和黑猩猩；犬科动物，如狗和狼；猫科动物，如猫、狮子和老虎；马科动物，如马、驴和斑马；食用动物，如牛、猪和绵羊；有蹄类动物，如鹿和长颈鹿；啮齿动物，如小鼠、大鼠、仓鼠和豚鼠等。在本实施例中，受试者为人。
实施例1突变体合成
通过Fmoc固相多肽合成技术，采用Rink MBHA树脂，以哌啶作为Fmoc保护基脱除试剂，HCTU和DIPEA作为偶联条件。本发明的活性多肽Mr1.1[S4Dap][S9Dap]及其它类似物可通过如下化学合成步骤所示流程方法合成。
所述方法包括如下步骤：
1.1用体积比为1：1的二氯甲烷、N，N-二甲基甲酰胺对树脂进行活化，然后遵循固相合成方法得到直链肽GCC(Dap)HPAC(Dap)VNNPDIC*(*代表C端酰胺化)；
1.2使用三氟乙酸、水、苯酚和三异丙基硅烷的混合溶液对树脂进行切割，三氟乙酸：水：苯酚：三异丙基硅烷＝88：5：5：2(V/V)，旋蒸除去三氟乙酸，加入冰乙醚，有白色固体析出，离心后的固体加水溶解，使用冻干机对其冻干，得到固体粉末；
1.3构建其中的两对二硫键，2位、8位半胱氨酸选用的巯基保护基为三苯甲基，3位、 16位的半胱氨酸选用的巯基保护基为乙酰胺甲基；
1.4对2位8位的二硫键进行构建：
采用空气氧化法，取50mg的固体粉末，以0.2mg/mL的浓度溶解在150mL 0.2M碳酸氢铵水溶液中，于250mL茄形瓶，电磁搅拌，室温条件下反应48h，使用冻干机得到白色固体粉末。
1.5对3位16位的二硫键进行构建：
称取10mg白色固体粉末溶于反应溶剂中，其中水：乙腈：TFA＝5：5：0.01，V/V，反应溶剂中加入3mL碘/乙腈溶液，使溶液保持发黄的状态，碘/乙腈溶液浓度为5mg/mL；于 50mL茄形瓶，室温搅拌反应30分钟后，加入浓度为5mg/mL的抗坏血酸水溶液，混匀，使溶液呈无色澄清，冻干后得到最终产物白色固体粉末。
实施例2电生理活性测试
使用体外转录试剂盒制备人α9α10乙酰胆碱受体的cRNA,其浓度UV260m下的OD值进行测算。解剖收集非洲爪蟾卵母细胞,在第一天和第二天将两个亚基的cRNA注射入蛙卵中, 注射量均为5ng，在ND-96中培养。注射后1-4天将表达了α9α10乙酰胆碱受体的卵母细胞用于电生理学活性测试。具体测试方法为：将1个注射过cRNA的爪蟾卵母细胞置于直径为4mm深度为2mm的30uL Sylgard记录槽中，重力灌注含有0.1mg/ml牛血清白蛋白(BSA) 的ND96灌流液(96.0mM NaC1，2.0mM KC1，1.8mM CaCl2 1.0mM MgCl2，5mM HEPES， pH 7.1-7.5)。所有的芋螺毒素溶液也含有0.1mg/mL BSA以减少非特异性吸附,用转换阀可以在灌注毒素或乙酰胆碱之间进行自由切换,ACh门控的电流由双电极电压钳放大器设置在“慢”档,以及clamp gain在最大值(×2000)位置时进行在线记录。用外径1mm内径0.75mm的玻璃毛细管拉制玻璃电极，并充满3M KCl作为电压和电流电极。膜电压钳制在-70mV，整个系统均由电脑控制和记录数据。ACh脉冲为每隔5min自动灌注1s的ACh，ACh的浓度为6μ M。每条多肽至少记录6个卵母细胞的电流反应情况，测试的电流数据用GraphPad Prism软件进行统计分析。
表1 Mr1.1及相关突变体类似物在人源及鼠源α9α10nAChRs的活性
通过测试Mr1.1及相关类似物针对人α9α10nAChR的抑制活性，由表1可以得出在4号引入Dap或者Dab都可以大幅度提高其对α9α10nAChR活性；在9号位引入Dap可以大幅度提高多肽对α9α10nAChR活性；在10号位引入R残基替代，也可以一定程度提高多肽对α9α10nAChR活性。结合表1、图1和图2可以看出，Mr1.1[S4Dap]单突变活性远高于野生型Mr1.1，然而组合可以提高Mr1.1活性的单突变，却通常不能获得超过Mr1.1[S4Dap]单突变的多突变组合。例如Mr1.1[S4Dap,V10Dap],Mr1.1[S9Dap,V10Dap],Mr1.1[S4Dap,S9Dap, V10Dap]的IC50均高于Mr1.1[S4Dap]单突变。其中组合4/9位的突变，可以获得 Mr1.1[S4Dap,S9Dap]的IC50＝0.85nM，显著低于Mr1.1[S4Dap]单突变的IC50，说明 Mr1.1[S4Dap,S9Dap]具有优选的生物活性。
针对作用于α9α10nAChR的芋螺毒素PeIA设计了[S4Dap]单突变体与[S4Dap,S9Dap] 双突变体。类似于Mr1.1，PeIA单突变体PeIA[S4Dap]的IC50＝5.3nM，比野生型PeIA活性提高了5倍，而PeIA的双突变体PeIA[S4Dap,S9Dap]活性在PeIA[S4Dap]基础上进一步提高了5倍，活性达到IC50＝0.93nM(图3，4)。因此，[S4Dap,S9Dap]双突变可以大幅度提高靶向α9α10nAChR芋螺毒素的活性。
实施例4动物体内镇痛活性的表征
镇痛活性的测试采用的是大鼠坐骨神经慢性压迫损伤(CCI)模型。于济南朋悦动物繁育中心购置24只120-150g的大鼠，分为四组进行适应性训练，训练一周待大鼠适应环境后，对其中两组进行造模，造模过程如下：大鼠经腹腔注射2％戊巴比妥钠麻醉后，剔除右腿鼠毛，无菌条件下切开右下肢皮肤1-2cm，钝性分离肌肉和筋膜，暴露坐骨神经主干，用4-0铬制羊肠线以间距为1mm打四个结，其松紧程度要求至大鼠脚趾微微抽搐为止，以不影响神经外膜的血运为度，结扎完成后用四万单位青霉素钠清洗伤口，最后缝合，术后连续三天在患肢肌肉注射4万单位的青霉素钠防止感染。其余两组中，一组作为空白对照，一组作为假手术组，只暴露坐骨神经主干而不进行结扎压迫，模拟伤口对大鼠痛阈的影响。待一周后两组造模大鼠的阈值降低到最低值后，进行连续两周的原位肌肉注射给药，一组每天注射生理盐水，另一组给野生型Mr1.1,Mr1.1-S4Dap，Mr1.1-[S4Dap,S9Dap]，给药剂量为25μg/kg。对于阳性药加巴喷丁，我们采用灌胃给药的给药方式，其用药剂量为60 mg/kg。给药后测试024h的镇痛活性，用IITC电子测痛仪测定大鼠的机械痛疼痛阈值，用IITC足底热点测痛仪测定大鼠的热敏痛疼痛阈值，热痛测试中，工作光强设置为“025”，待机光强设置为“010”，预置时间设置为“20”，获得的数据用GraphPad Prism软件进行统计分析。
我们建立了大鼠坐骨神经慢性压迫损伤(CCI)模型，并测试了Mr1.1及类似物Mr1.1[S4Dap]和Mr1.1[S4Dap,S9Dap]在CCI大鼠上的针对机械痛的镇痛活性。
测试了以25μg/kg肌肉注射给药剂量的Mr1.1及相关类似物在CCI大鼠上的镇痛活性，其阳性对照选用的是市场上用于治疗神经痛的药物加巴喷丁(60 mg/kg剂量口服给药)，测试了单次给药后24h内多次测定大鼠的机械痛足爪缩回阈值(PWT)。
表2.动物分组级给药实验设计
| 组别 | 动物数量 | 给药剂量 | 给药方式 | 给药天数 |
| Saline | 8 | - | - | 7 |
| Gabapentin | 8 | 60 mg/kg | p.o | 7 |
| Mr1.1 | 8 | 25μg/kg | i.m | 7 |
| Mr1.1[S4Dap] | 8 | 25μg/kg | i.m | 7 |
| Mr1.1[S4Dap,S9Dap] | 8 | 25μg/kg | i.m | 7 |
如图5所示，从机械痛数据来看，无论Mr1.1单突变体类似物Mr1.1[S4Dap]还是其双突变体类似物Mr1.1[S4Dap,S9Dap]，体内镇痛活性显著优于野生型芋螺毒素Mr1.1。在25μg/kg 肌肉注射给药剂量下，Mr1.1[S4Dap,S9Dap]的镇痛效果不仅优于Mr1.1[S4Dap]，而且优于阳性药加巴喷丁(Gabapentin，60mg/kg口服给药)。综上，Mr1.1的4/9号位的[SDap]双突变具有协同作用，不但可以提高多肽的体外活性，而且可以提高多肽的体内镇痛活性。
Claims (10)
1.一种作用于α9α10nAChR的芋螺毒素的突变体多肽,所述芋螺毒素的突变体多肽包含第4、第9或第10位点及其相互组合位点的氨基酸突变。
2.如权利要求2所述的芋螺毒素的突变体多肽，所述位点的氨基酸突变是指由丝氨酸突变为Dap。
3.如权利要求3所述的芋螺毒素的突变体多肽，所述第4位和第9位同时由丝氨酸突变为Dap的突变体为[S4Dap,S9Dap]。
4.包含权利要求1-7任一项所述芋螺毒素的突变体多肽的组合物，所述组合物可以包含制剂所需的载体或辅料。
5.包含权利要求1-7任一项所述芋螺毒素的突变体多肽的融合蛋白，所述融合蛋白通过linker或连接臂将芋螺毒素的突变体多肽与其它序列连接。
6.编码权利要求1-7任一项所述芋螺毒素的突变体多肽的核酸分子。
7.表达权利要求1-7任一项所述芋螺毒素的构建体，所述构建体包含其核酸分子。
8.表达权利要求1-7任一项所述芋螺毒素的宿主细胞。
9.包含权利要求1-7任一项所述融芋螺毒素的突变体多肽的药物组合物，所述药物组合物包含药学上可接受的辅料。
10.权利要求1-7任一项所述芋螺毒素的突变体多肽在制备治疗或预防由α9α10nAChR受体介导的疾病或病症中的应用，其中所述疾病或病症包括神经痛、成瘾、帕金森症、癫痫症、局部缺血、兴奋性神经元细胞死亡、痴呆、乳腺癌、肺癌、脑脊髓炎、癌症与癌症化疗、化疗药物诱导痛、酒精中毒、坐骨神经痛、糖尿病诱发痛、三叉神经痛、硬化症、带状疱疹痛、机械伤和手术伤、艾滋病诱发痛、头部神经瘫痪、药物中毒、工业污染中毒、淋巴神经痛、骨髓瘤、多点运动神经痛、慢性先天性感觉神经病、急性剧烈自发性神经痛、挤压神经痛、脉管炎、血管炎、局部缺血、尿毒症、儿童胆汁、肝脏疾病、慢性呼吸障碍、复合神经痛、多器官衰竭、脓毒病/脓血症、肝炎、卟啉症、维生素缺乏、慢性肝脏病、原生胆汁硬化、高血脂症、麻疯病、莱姆关节炎、感觉神经束膜炎或过敏症。
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|---|---|---|---|---|
| US6077680A (en) * | 1996-11-27 | 2000-06-20 | The University Of Florida | ShK toxin compositions and methods of use |
| CN114573674A (zh) * | 2020-12-01 | 2022-06-03 | 中国海洋大学 | 一种α9α10 nAChR抑制活性肽及其应用 |
| CN115246872A (zh) * | 2021-04-27 | 2022-10-28 | 中国海洋大学 | 一种芋螺毒素突变体及其制备方法和应用 |
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| US6077680A (en) * | 1996-11-27 | 2000-06-20 | The University Of Florida | ShK toxin compositions and methods of use |
| CN114573674A (zh) * | 2020-12-01 | 2022-06-03 | 中国海洋大学 | 一种α9α10 nAChR抑制活性肽及其应用 |
| CN115246872A (zh) * | 2021-04-27 | 2022-10-28 | 中国海洋大学 | 一种芋螺毒素突变体及其制备方法和应用 |
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| RILEI YU等: "Molecular Determinants Conferring the Stoichiometric-Dependent Activity of α‑Conotoxins at the Human α9α10 Nicotinic Acetylcholine Receptor Subtype", JOURNAL OF MEDICINAL CHEMISTRY, vol. 61, 7 May 2018 (2018-05-07), pages 4628 - 4634 * |
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