CN113072620B - 一种具有镇痛活性的pd-1靶向肽、其合成方法及其应用 - Google Patents
一种具有镇痛活性的pd-1靶向肽、其合成方法及其应用 Download PDFInfo
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Abstract
本发明属于生物医药技术领域，本发明公开了一种靶向PD‑1的小分子镇痛肽TP‑01，其氨基酸序列为：ISYGGADYK，分子量为973.04g/mol。该小分子多肽可通过经典的Fmoc‑固相合成得的，在PD‑1靶点镇痛药物的研发中发挥重要作用。本发明的优点在于首次通过分子对接技术，以PD‑1为靶点高通量筛选内部肽库，筛选出具有镇痛活性的PD‑1的小分子肽TP‑01。本发明所提供的化合物能够显著性抑制高K+溶液诱导的钙离子内流；此外，在小鼠疼痛模型中表现出很好的镇痛活性，能够有效缓解炎症痛及内脏痛，从而填补了PD‑1为靶点的镇痛肽类药物的研究空白，为基于PD‑1镇痛药物的研究和开发提供了新的思路以及理论依据。
Description
技术领域
本发明属于生物医药技术领域，具体涉及一种具有镇痛活性的PD-1靶向肽、其合成方法及其应用。
背景技术
疼痛是一种重要的生理现象，它能够提醒机体已经出现或潜在的组织损伤，也是许多临床疾病的常见症状。慢性痛是一种全球性的健康问题，在世界范围内的发病率高达1/3，每年用于治疗慢性疼痛的费用高达60000多亿美元，不仅降低了患者的生活质量，而且造成严重的经济和社会问题(Pain.2019，160，53–59)。
当前针对慢性疼痛的治疗以抗癫痫药、抗抑郁药、阿片类药物(如吗啡)、辣椒素、肉毒杆菌和非甾体抗炎药物(如阿司匹林)等药物治疗为主。但这些药物的治疗效果有限，且伴随药物耐受、药物依赖、呼吸抑制、胃肠道功能抑制、以及痛觉过敏等不良反应。开发安全有效的治疗慢性疼痛的药物的需求日益迫切。
程序性死亡受体(PD-1)/程序性死亡配体(PD-L1)通路最早在人类的癌症治疗中发现，在肿瘤的微环境中，活化的T细胞高水平的表达PD-1，通过干扰素γ(IFN-γ)、白介素(ILs)和肿瘤坏死因子-α(TNF-α)等细胞因子的释放，能够诱导PD-L1在局部组织中的表达，上调的PD-1通过结合T细胞上的PD-1后，阻止T细胞的过度兴奋，维持免疫系统对自身抗原的耐受，并降低对正常组织的免疫反应(Immunity.2018，48，434–452)。通过阻断恶性肿瘤和免疫T细胞间PD-1/PD-L1的相互作用，可以逆转免疫抑制状态，提高机体免疫细胞对肿瘤细胞的杀伤能力。因此，免疫检查点PD-1/PD-L1通路，作为恶性肿瘤的治疗靶点，在免疫治疗领域脱颖而出。2014年，首个PD-1单克隆抗体药物纳武单抗被批准用于治疗黑色素瘤。
最新研究发现PD-1和在中枢和外周神经系统中广泛表达，参与疼痛的调控。PD-L1通过激活PD-1，诱发SHP-1磷酸化，抑制钠通道，活化钾通道，进而抑制疼痛信号的传递。足底皮下注射PD-L1能够显著缓解急性痛和慢性痛，具有很好的应用前景及安全性(Nat.Neurosci.2017，20，917-926)。因此，寻找具有镇痛活性的PD-1为靶点的多肽配体，为开发新型镇痛药物提供新的思路。
发明内容
发明目的：针对现有技术中存在问题或不足，本发明提供一种具有镇痛活性的PD-1靶向肽、其合成方法及其应用。
为实现上述发明目的，本发明的实施例提供一种具有镇痛活性的PD-1靶向肽，其特征在于，所述PD-1靶向肽为小分子多肽TP-01，其能够特异性的结合于PD-1的IgV区，其氨基酸序列为：ISYGGADYK，即Ile-Ser-Tyr-Gly-Gly-Ala-Asp-Tyr-Lys，分子量为973.04g/mol。
本发明的实施例还一种具有镇痛活性的PD-1靶向肽的合成方法，其特征在于，包括以下步骤：
(1)选取经过二氯甲烷溶胀处理后的wang-树脂作为多肽合成载体；
(2)20％六氢吡啶的N，N-二甲基甲酰胺混合溶液作为9-芴甲氧羰基的脱除试剂；
(3)N，N-二异丙基乙胺/1-羟基苯并三唑/O-苯并三氮唑-四甲基脲六氟磷酸盐作为多肽合成的缩合试剂，所用量为树脂物质的量的3～6倍；
(4)从肽序列的C端开始，依次在树脂上接入N-alpha-芴甲氧羰基-N-epsilon-叔丁氧羰基-L-赖氨酸、N-芴甲氧羰基-O-叔丁基-L-酪氨酸、N-芴甲氧羰基-L-天冬氨酸-4-叔丁酯、N-芴甲氧羰基-L-丙氨酸、N-芴甲氧羰基-甘氨酸、N-芴甲氧羰基-甘氨酸、N-芴甲氧羰基-O-叔丁基-L-酪氨酸、N-芴甲氧羰基-L-丝氨酸以及N-芴甲氧羰基-L-异亮氨酸，所用量为树脂物质量的1.5～3倍；
(5)所得粗肽树脂经过二氯甲烷溶胀/无水甲醇压缩反复多次，采用切割试剂从肽树脂上获得粗肽、冷冻干燥、RP-HPLC制备柱纯化，得到白色固体TP-01，产率65％。
进一步的，所述步骤(5)中，切割试剂为三氟乙酸/三异丙基硅烷/双蒸水＝95:2.5:2.5。
进一步的，所述步骤(2)中，洗脱时间为15min，分3次，5min/次进行洗脱。
进一步的，整个合成反应在氩气保护下进行。
本发明的实施例另外还提供一种具有镇痛活性的PD-1靶向肽在疼痛治疗领域的应用。
优选的，所述PD-1靶向肽TP-01对疼痛信号传导具有抑制效果并能显著缓解炎症痛。
优选的，所述靶向肽TP-01能够通过结合PD-1，激活SHP-1信号通路，诱发强效的镇痛作用。
本发明的实施例另外还提供一种具有镇痛活性的PD-1靶向肽在制备疼痛治疗药物方面的应用。
优选的，所述疼痛治疗药物以靶向肽TP-01作为活性成分，还包括制药学上可接受的载体或添加剂。本发明所提供具有镇痛活性的PD-1靶向肽在制备疼痛治疗药物方面的应用，该药物为可缓解内脏痛的药物和治疗慢性痛的药物。其制备方法是以该靶向肽TP-01作为活性成分，加上制药学上可接受的载体或添加剂，按常规方法制备成抗肿瘤药物制剂即可。
本发明的上述技术方案的有益效果如下：
(1)本发明公开的TP-01，首次通过分子对接技术从多肽数据库中筛选能够结合PD-1，具有镇痛效果的小分子肽，相比于当前市场上的PD-L1，本发明的TP-01合成方法便捷，容易操作，可做大量合成，易纯化等特点；此外合成TP-01的氨基酸为常见氨基酸，在市场上容易购买得到，且价格低廉，从合成成本方面来看，降低了其应用于镇痛药物中的成本。7
(2)本发明公开的TP-01，其作用靶点为最新研究发现的PD-1。相比于以往的阿片受体为靶点的药物，TP-01规避了激活阿片受体，诱发成瘾、耐受、便秘及呼吸抑制等不良反应的风险，本发明公开的TP-01的安全性高，具有更好的临床应用前景。
(3)本发明的实施例通过钙成像实验，证明了PD-1靶向肽TP-01显著性抑制胞外Ca2+内流，继而调控疼痛相关的神经递质的释放。本发明的实施例还通过在小鼠的福尔马林诱导的炎症痛和内脏痛模型中，证明TP-01具有很好的缓解炎症痛和内脏痛的效果。本发明为基于PD-1的药物研究和开发提供了新思路和理论基础。
附图说明
图1为本发明的实施例中TP-01与PD-1分子对接结果图。
图2为本发明的实施例中TP-01质谱鉴定图。
图3为本发明的实施例中TP-01对高K+诱导的Ca2+内流的抑制结果图。其中，图3A为高K+溶液刺激对照组和TP-01介导的DRG神经元Ca2+变化曲线图；图3B为对照组和TP-01介导的干扰组Ca2+变化的统计学分析图，*表示与对照组的比较，P<0.05。
图4为本发明的实施例中TP-01对福尔马林诱导的炎症痛的缓解作用结果图。
图5为本发明的实施例中TP-01对醋酸诱导的内脏痛的缓解作用结果图。其中，图5A为醋酸扭体实验中鞘内注射不同剂量TP-01时小鼠扭体次数比较图；图5B为鞘内注射30μg TP-01时，对照组小鼠、Pd1敲除小鼠或SHP-1拮抗剂小鼠在醋酸扭体实验中小鼠扭体次数比较图。
具体实施方式
为使本发明要解决的技术问题、技术方案和优点更加清楚，下面将结合具体实施例进行详细描述。
本发明所述的就有镇痛活性的PD-1靶向肽TP-01，是基于分子对接技术从内部多肽数据库筛选得到的多肽，该靶向肽TP-01的氨基酸序列为：
Ile-Ser-Tyr-Gly-Gly-Ala-Asp-Tyr-Lys；分子量为973.04g/mol。
本发明中，TP-01与PD-1分子对接结果如图1所示。
实施例1 PD-1靶向肽TP-01采用经典的Fmoc-固相和成方法合成
本发明PD-1靶向肽TP-01采用经典的Fmoc-固相和成方法合成，具体包括以下步骤：
选取经过二氯甲烷溶胀处理后的wang-树脂作为多肽合成载体。整个合成反应在氩气保护下进行。20％六氢吡啶的N，N-二甲基甲酰胺混合溶液作为9-芴甲氧羰基(Fmoc)的脱除试剂，洗脱时间为15min(3次，5min/次)。N，N-二异丙基乙胺/1-羟基苯并三唑/O-苯并三氮唑-四甲基脲六氟磷酸盐作为多肽合成的缩合试剂，所用量为树脂物质的量的3～6倍。切割试剂为三氟乙酸/三异丙基硅烷/双蒸水＝95:2.5:2.5。本发明中，氨基酸偶联试剂的组合比例，氨基保护基团的脱除试剂组分及比例，茚检试剂的配方及比例以及切割试剂的组分比例，为本领域技术人员公知的技术。
从肽序列的C端开始，依次在树脂上接入N-alpha-芴甲氧羰基-N-epsilon-叔丁氧羰基-L-赖氨酸、N-芴甲氧羰基-O-叔丁基-L-酪氨酸、N-芴甲氧羰基-L-天冬氨酸-4-叔丁酯、N-芴甲氧羰基-L-丙氨酸、N-芴甲氧羰基-甘氨酸、N-芴甲氧羰基-甘氨酸、N-芴甲氧羰基-O-叔丁基-L-酪氨酸、N-芴甲氧羰基-L-丝氨酸以及N-芴甲氧羰基-L-异亮氨酸，所用量为树脂物质量的1.5～3倍。所得粗肽树脂经过二氯甲烷溶胀/无水甲醇压缩反复多次，采用切割试剂从肽树脂上获得粗肽、冷冻干燥、RP-HPLC制备柱纯化，得到白色固体TP-01，产率65％。通过质谱仪和RP-HPLC分析柱鉴定，TP-01质谱图如图2所示。
TP-01结构式如下：
本发明的TP-01肽序列、分子量、Amber打分及其纯度如表1所示：
表1 TP-01肽序列、分子量、Amber打分及其纯度表
| 名称 | 序列 | 分子量 | Amber打分 | 纯度(％) |
| TP-01 | ISYGGADYK | 973.04 | -90.0 | 96 |
本发明的氨基酸缩写如表2所示：
表2 TP-01的氨基酸缩写一览表
| I | Ile | 异亮氨酸 |
| S | Ser | 丝氨酸 |
| Y | Tyr | 酪氨酸 |
| G | Gly | 甘氨酸 |
| A | Ala | 丙氨酸 |
| D | Asp | 天冬氨酸 |
| K | Lys | 赖氨酸 |
实施例2 DRG神经元钙成技术鉴定PD-1靶向肽对疼痛信号传导的抑制效果
通过DRG神经元钙成技术鉴定PD-1靶向肽对疼痛信号传导的抑制效果，具体包括以下步骤：
通过急性分离提取3周雌性小鼠的DRG神经元。Neurobasal培养基(含2％B27，Clutanine 1％，以及1％青霉素-链霉素双抗溶液)体外培养细胞48h。利用Flou-4/AM荧光探针标记DRG神经元，在TP-01预处理后，经高K+溶液刺激DRG神经元，通过激光共聚焦技术检测细胞内游离的Ca2+水平的变化。
DRG神经元内游离的Ca2+与神经兴奋性和突触间信号传递密切关联，参与疼痛信息的调控。外界的各种刺激如高钾或高糖溶液会导致胞质Ca2+浓度的变化，胞内Ca2+水平高低直接影响着疼痛阈值。
钙成像的实验结果：如图3A和图3B所示，TP-01对高K+诱发的DRG神经元Ca2+胞内浓度的升高具有显著性的抑制作用，说明TP-01参与疼痛信号的调控。PD-1靶向镇痛肽TP-01能够明显抑制DRG神经元胞外的Ca2+进入胞内，证实其能够调控疼痛信号的传递。
实施例3福尔马林诱导的炎症痛实验
福尔马林诱导的炎症痛实验，具体包括以下步骤：
本发明选择体重20～25g的ICR小鼠，利用福尔马林实验来检测TP-01在制备镇痛药物中应用。根据不同疼痛反应阶段，福尔马林诱导的疼痛分为两相。0-10min为I相痛；10-45min为II相痛。通过鞘内给药方式注射PD-1靶向镇痛肽TP-01，0.9％的生理盐水作为阴性对照组，给药5min后，在小鼠的后左爪注射20μl 5％的福尔马林溶液。统计小鼠在0-10min和10-45min时间段的舔/咬/甩注射足的累积时间。
实验结果见图4。通过鞘内给药，在最低1μg剂量下，TP-01也表现出显著的缓解炎症痛的作用。相比于由针头刺破皮肤所引起的I相痛，TP-01对炎症因子引发的II痛效果最显著。
实施例4醋酸扭体实验
脏器中的痛觉感受器被激活后产生的疼痛响应，称为内脏痛，如心绞痛，腹绞痛，消化不良，胰腺炎，阑尾炎，痛经，子宫切除和肿瘤侵袭等，在临床上治疗的疼痛中占有很大的比例。由腹腔注射的醋酸溶液诱导小鼠产生炎症因子导致的持久的内脏痛，表现为伴随有小鼠后肢过度伸展的腹部抽搐，是一种经典的急性腹腔内脏痛模型，其与临床上人的肠道疼痛模型相关性很高。医学上常被用来评估阿片类药物在内脏痛模型中镇痛效果的经典疼痛模型。因此，本发明通过醋酸扭体实验，来检测TP-01在制备内脏痛镇痛药物中的应用，具体包括以下步骤：
首先，本发明通过鞘内注射TP-01，生理盐水组做为阴性对照组，5min后腹腔注射0.1％的冰醋酸(10mL/kg)，统计20min内小鼠的扭体次数。
实验结果见图5。TP-01对0.1％剂量醋酸溶液诱导的内脏痛具有强效的、剂量依赖的镇痛作用，图5A所示，鞘内给药后，在小鼠醋酸诱导的扭体实验中，TP-01表现出剂量依赖的镇痛效果，在30μg剂量下，对小鼠扭体行为抑制率高达82％，鞘内注射30μg TP-01能够有效抑制内脏痛。但是，如图5B所示，在Pd1敲除小鼠和SHP-1的拮抗剂SSG预处理小鼠，30μg剂量下的TP-01高镇痛作用，这种强效镇痛效果显著性的衰减，证实TP-01是通过激活PD-1，诱发下游SHP-1信号通路，产生高镇痛作用。
综上，本发明通过分子对接技术从内部多肽数据库筛选得到的TP-01，能够通过结合PD-1，激活SHP-1信号通路，诱发强效的镇痛作用，在制备镇痛药物方面具有很好的临床应用前景。
以上所述是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明所述原理的前提下，还可以作出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
Claims (5)
1.一种具有镇痛活性的PD-1靶向肽，其特征在于，所述PD-1靶向肽为小分子多肽TP-01，其能够特异性的结合于PD-1的IgV区，其氨基酸序列为：ISYGGADYK，即Ile-Ser-Tyr-Gly-Gly-Ala-Asp-Tyr-Lys，分子量为973.04 g/mol。
2.一种具有镇痛活性的PD-1靶向肽的合成方法，其特征在于，包括以下步骤：
（1）选取经过二氯甲烷溶胀处理后的 wang-树脂作为多肽合成载体；
（2）20% 六氢吡啶的 N，N-二甲基甲酰胺混合溶液作为 9-芴甲氧羰基的脱除试剂；
（3）N，N-二异丙基乙胺/ 1-羟基苯并三唑/ O-苯并三氮唑-四甲基脲六氟磷酸盐作为多肽合成的缩合试剂，所用量为树脂物质的量的 3~6 倍；
（4）从肽序列的 C 端开始，依次在树脂上接入 N-alpha-芴甲氧羰基-N-epsilon-叔丁氧羰基-L-赖氨酸、N-芴甲氧羰基-O-叔丁基-L-酪氨酸、N-芴甲氧羰基-L-天冬氨酸-4-叔丁酯、N-芴甲氧羰基-L-丙氨酸、N-芴甲氧羰基-甘氨酸、N-芴甲氧羰基-甘氨酸、N-芴甲氧羰基-O-叔丁基-L-酪氨酸、N-芴甲氧羰基-L-丝氨酸以及 N-芴甲氧羰基-L-异亮氨酸，所用量为树脂物质量的 1.5~3 倍；
（5）所得粗肽树脂经过二氯甲烷溶胀/无水甲醇压缩反复多次，采用切割试剂从肽树脂上获得粗肽、冷冻干燥、RP-HPLC 制备柱纯化，得到白色固体 TP-01，产率 65%。
3.根据权利要求2所述的一种具有镇痛活性的PD-1靶向肽的合成方法，其特征在于，所述步骤（5）中，切割试剂为三氟乙酸/三异丙基硅烷/ 双蒸水=95:2.5:2.5。
4.根据权利要求2所述的一种具有镇痛活性的PD-1靶向肽的合成方法，其特征在于，所述步骤（2）中，洗脱时间为 15 min，分3 次，5min/次进行洗脱。
5.根据权利要求2所述的一种具有镇痛活性的PD-1靶向肽的合成方法，其特征在于，整个合成反应在氩气保护下进行。
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| CN108059649A (zh) * | 2016-11-09 | 2018-05-22 | 理查德艾伦科学公司 | 蛋白组基因组分析系统和方法 |
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| WO2018145020A1 (en) * | 2017-02-03 | 2018-08-09 | The Medical College Of Wisconsin, Inc. | Kras peptide vaccine compositions and method of use |
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| "PD-L1 inhibits acute and chronic pain by suppressing nociceptive neuron activity via PD-1";Gang Chen等;《Nat Neurosci.》;20170731;第20卷(第7期);摘要，第12页 * |
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