CN115403661A - 一种PTP1B多肽抑制剂BimBH3-12-G9A及其应用 - Google Patents
一种PTP1B多肽抑制剂BimBH3-12-G9A及其应用 Download PDFInfo
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- CN115403661A CN115403661A CN202210965782.7A CN202210965782A CN115403661A CN 115403661 A CN115403661 A CN 115403661A CN 202210965782 A CN202210965782 A CN 202210965782A CN 115403661 A CN115403661 A CN 115403661A
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Abstract
本发明公开了一种PTP1B多肽抑制剂BimBH3‑12‑G9A，所述多肽抑制剂的结构式如下：
该模拟肽化合物衍生自BimBH3结构域的核心12肽，其中第9位的Gly(G)被Ala(A)所替换，采用多肽固相合成方法进行制备，其结构中的氨基酸均为天然氨基酸。所述PTP1B多肽抑制剂BimBH3‑12‑G9A具有显著的抑制PTP1B的活性，在以PTP1B为靶点的相关疾病如糖尿病、癌症、阿尔兹海默症等的药物开发中具有潜在的应用价值。
Description
技术领域
本发明属于生物医药领域，具体涉及一种PTP1B多肽抑制剂 BimBH3-12-G9A及其应用。
背景技术
蛋白酪氨酸磷酸酶1B(protein tyrosine phosphatase 1B，PTP1B)与2型糖尿病及肥胖症的发病和发展有密切的关系，其是胰岛素信号转导通路中的关键的负调 节蛋白。PTP1B异常过量表达，会使胰岛素敏感性降低，形成胰岛素抵抗。而 PTP1B抑制剂能够通过阻断胰岛素刺激的胰岛素受体(IR)的酪氨酸磷酸化， 进而影响胰岛素受体底物(IRS-1)的磷酸化，使类胰岛素和胰岛素敏感性增强， 有效地从源头改善胰岛素抵抗，从而降低血糖，同时不存在胰岛素类药物的低血 糖不良反应。因此，PTP1B也是近年来研究T2DM的热门靶点，并且已有多个 候选化合物已进入临床前及临床I、II期实验。近年来的最新研究观点表明： PTP1B可以作为抗肿瘤和阿尔兹海默症药物开发的(潜在)靶标。一些研究发 现PTP1B过表达能够显著促进小鼠体内肿瘤的发生和生长，通过抑制剂抑制 PTP1B的表达能够产生抗肿瘤效果；机制研究发现PTP1B通过调控RNF213基 因从而控制细胞非线粒体氧消耗，进而促进缺氧条件下肿瘤细胞的生存和生长。 据此，PTP1B被看作是抗肿瘤药物的靶标。近些年PTP1B还被作为中枢神经系 统中与阿尔兹海默症相关生理过程中的调控作用，提出通过抑制PTP1B进而拮 抗PTP1B调控的与阿尔兹海默症相关的有害生理过程的策略，进行抗阿尔兹海 默症药物的研发。因此，PTP1B已成为抗糖尿病、癌症及阿尔兹海默症药物开 发的潜在热门靶点，而PTP1B抑制剂有望应用于以PTP1B为靶点的抗糖尿病、 癌症和阿尔兹海默症等药物的开发中。
目前，PTP1B的抑制剂主要包括无机小分子类化合物、有机化合物和天然 产物中PTP1B抑制剂。但无机小分子类化合物的选择性非常低，对所有的PTPs 都有较强的抑制性；而有机化合物大多通过有机合成和组合化学的方法进行筛 选，先筛选到具有抑制PTP1B活性的化合物，再对化合物的取代基团进行修饰， 最后得到一种较好的PTP1B抑制剂，此类抑制剂存在稳定性差、带电荷较高、 亲脂系数过高等制约成药性的问题；天然产物中PTP1B抑制剂是通过对自然界 中分离鉴定的天然产物进行高通量筛选，虽然其具有高选择性和活性，但作用位 点并不是很明确。因此，弥补现有PTP1B抑制分子的缺陷，开发结构新颖、选择性强、低毒且高效的新型PTP1B抑制剂以满足国内临床上的迫切需求，就显 得十分必要。
发明内容
本发明提供了一种PTP1B多肽抑制剂BimBH3-12-G9A及其应用。所述 PTP1B多肽抑制剂BimBH3-12-G9A具有显著的PTP1B的抑制活性，可用于制 备预防或治疗以PTP1B为靶点的相关疾病的药物开发。
为实现上述发明目的，本发明采用以下技术方案予以实现：
本发明提供了一种抑制PTP1B活性的新型BH3模拟肽类似物，所述新型 BH3模拟肽类似物的结构式如下：
其中，R1为长链羧酸，R2为COOH，R3为不同碳链长度的羧酸或多羧酸。
本发明提供了一种PTP1B多肽抑制剂BimBH3-12-G9A，所述多肽抑制剂的 结构式如下：：
进一步的，所述PTP1B多肽抑制剂BimBH3-12-G9A的制备方法包括以下步 骤：
(1)室温下，将Fmoc-Phe-Wang树脂置于手动多肽固相合成器中，用二氯 甲烷、二甲基甲酰胺活化；
(2)加入哌啶/二甲基甲酰胺混合液脱除Fmoc保护基；
(3)加入3-4倍树脂摩尔量的N-Fmoc保护氨基酸或羧酸、HOBT、HBTU 以及5-6倍树脂摩尔量的DIEA，室温振荡反应2～4h；
(4)重复步骤(2)和(3)，直至完成整个模拟肽序列的合成；
(5)将步骤(4)的产物中加入裂解液，室温搅拌，过滤，加入无水乙醚析 出固体后，经洗涤、真空干燥得模拟肽类似物粗产物；
(6)所述肽类似物粗产物使用反相制备液相色谱纯化，收集目标峰流动相 溶液脱去乙腈后，冷冻干燥得到絮状或粉末状固体，即得PTP1B多肽抑制剂 BimBH3-12-G9A纯品。
进一步的，所述裂解液包括苯酚、水、苯甲硫醚和三氟乙酸。
进一步的，所述步骤(5)中过滤后鼓吹N2去除多余的三氟乙酸。
本发明还提供了以所述的PTP1B多肽抑制剂BimBH3-12-G9A为活性成分的 药物或药物组合物，包括任一所述PTP1B多肽抑制剂BimBH3-12-G9A和一种或 多种药学上可接受的载体或赋型剂。
本发明还提供了所述的PTP1B多肽抑制剂BimBH3-12-G9A在制备用于抑制 PTP1B活性的抑制剂中的应用。
本发明还提供了所述的PTP1B多肽抑制剂BimBH3-12-G9A在制备用于预防 或治疗以PTP1B为靶点的疾病的药物中的应用。
进一步的，所述疾病包括糖尿病、癌症和阿尔兹海默症。
进一步的，以PTP1B多肽抑制剂BimBH3-12-G9A为活性成分的药物或药物 组合物的给药方式为口服或注射。
与现有技术相比，本发明的优点和技术效果是：本发明通过多肽固相合成方 法得到一种PTP1B多肽抑制剂BimBH3-12-G9A，该模拟肽化合物衍生自 BimBH3结构域的核心12肽，其中第9位的Gly被Ala所替换，采用多肽固相 合成方法进行制备，其结构中的氨基酸均为天然氨基酸。所述新型BH3模拟肽 类似物具有显著的抑制PTP1B的活性，在以PTP1B为靶点的相关疾病如糖尿病、 癌症、阿尔兹海默症等的药物开发中具有潜在的应用价值。因此，所述的PTP1B 多肽抑制剂分子BimBH3-12-G9A具有潜在的应用价值及很好的开发前景。
附图说明
图1为所述的PTP1B多肽抑制剂分子BimBH3-12-G9A(即scan-8)对靶蛋 白PTP1B的剂量-抑制效应曲线。
具体实施方式
以下结合具体实施例对本发明的技术方案做进一步详细的说明。下述实施例 中的方法，如无特别说明，均为常规方法。
实施例1
以scan-1为例的合成路线，具体制备过程如下：
(1)树脂活化：称取相应量的Fmoc-Phe-Wang(scan-11为Fmoc-Ala-Wang) 树脂置于手动多肽固相合成器中，DCM洗4次，加入5ml DCM溶涨活化3h， DMF洗4次，加入20％哌啶DMF脱去Fmoc保护基两次(20min+5min)，5ml DMF洗4次，5ml DCM洗4次，Kaiser’s试剂检测。
(2)连接Phe(F)：DMF洗涤3次，分别加入3倍树脂摩尔量的Fmoc-Phe-OH、 HBTU、HOBt和6倍树脂摩尔量的DIEA，溶于10ml DMF中，室温搅拌反应 2h，DMF洗4次，加入20％哌啶DMF脱去Fmoc保护基两次(20min+5min)， 5ml DMF洗4次，5ml DCM洗4次，Kaiser’s试剂检测。
(3)连接Glu(E)：DMF洗涤3次，分别加入3倍树脂摩尔量的 Fmoc-Glu(OtBu)-OH、HBTU、HOBt和6倍树脂摩尔量的DIEA，溶于10ml DMF 中，室温搅拌反应2h，DMF洗4次，加入20％哌啶DMF脱去Fmoc保护基两 次(20min+5min)，5ml DMF洗4次，5ml DCM洗4次，Kaiser’s试剂检测。
(4)连接Asp(D)：DMF洗涤3次，分别加入3倍树脂摩尔量的 Fmoc-Asp(OtBu)-OH、HBTU、HOBt和6倍树脂摩尔量的DIEA，溶于10ml DMF 中，室温搅拌反应2h，DMF洗4次，加入20％哌啶DMF脱去Fmoc保护基两 次(20min+5min)，5ml DMF洗4次，5ml DCM洗4次，Kaiser’s试剂检测。
(5)连接Gly(G)：DMF洗涤3次，分别加入3倍树脂摩尔量的Fmoc-Gly-OH、 HBTU、HOBt和6倍树脂摩尔量的DIEA，溶于10ml DMF中，室温搅拌反应 2h，DMF洗4次，加入20％哌啶DMF脱去Fmoc保护基两次(20min+5min)， 5ml DMF洗4次，5ml DCM洗4次，Kaiser’s试剂检测。
(6)连接Ile(I)：DMF洗涤3次，分别加入3倍树脂摩尔量的Fmoc-Ile-OH、 HBTU、HOBt和6倍树脂摩尔量的DIEA，溶于10ml DMF中，室温搅拌反应 2h，DMF洗4次，加入20％哌啶DMF脱去Fmoc保护基两次(20min+5min)， 5ml DMF洗4次，5ml DCM洗4次，Kaiser’s试剂检测。
(7)连接Arg(R)：DMF洗涤3次，分别加入3倍树脂摩尔量的Fmoc- Arg(Mtr)-OH、HBTU、HOBt和6倍树脂摩尔量的DIEA，溶于10ml DMF中， 室温搅拌反应2h，DMF洗4次，加入20％哌啶DMF脱去Fmoc保护基两次 (20min+5min)，5ml DMF洗4次，5ml DCM洗4次，Kaiser’s试剂检测。重 复此步骤1次。
(8)连接Arg(R)：DMF洗涤3次，分别加入3倍树脂摩尔量的Fmoc- Arg(Mtr)-OH、HBTU、HOBt和6倍树脂摩尔量的DIEA，溶于10ml DMF中， 室温搅拌反应2h，DMF洗4次，加入20％哌啶DMF脱去Fmoc保护基两次 (20min+5min)，5ml DMF洗4次，5ml DCM洗4次，Kaiser’s试剂检测。重 复此步骤1次。
(9)连接Leu(L)：DMF洗涤3次，分别加入3倍树脂摩尔量的Fmoc-Leu-OH、 HBTU、HOBt和6倍树脂摩尔量的DIEA，溶于10ml DMF中，室温搅拌反应 2h，DMF洗4次，加入20％哌啶DMF脱去Fmoc保护基两次(20min+5min)， 5ml DMF洗4次，5ml DCM洗4次，Kaiser’s试剂检测。
(10)连接Glu(E)：DMF洗涤3次，分别加入3倍树脂摩尔量的 Fmoc-Glu(OtBu)-OH、HBTU、HOBt和6倍树脂摩尔量的DIEA，溶于10ml DMF 中，室温搅拌反应2h，DMF洗4次，加入20％哌啶DMF脱去Fmoc保护基两 次(20min+5min)，5ml DMF洗4次，5ml DCM洗4次，Kaiser’s试剂检测。
(11)连接Glu(Q)：DMF洗涤3次，分别加入3倍树脂摩尔量的 Fmoc-Glu(OtBu)-OH、HBTU、HOBt和6倍树脂摩尔量的DIEA，溶于10ml DMF 中，室温搅拌反应2h，DMF洗4次，加入20％哌啶DMF脱去Fmoc保护基两 次(20min+5min)，5ml DMF洗4次，5ml DCM洗4次，Kaiser’s试剂检测。
(12)连接Ala(A)：DMF洗涤3次，分别加入3倍树脂摩尔量的 Fmoc-Ala-OH、HBTU、HOBt和6倍树脂摩尔量的DIEA，溶于10ml DMF中， 室温搅拌反应2h，DMF洗4次，加入20％哌啶DMF脱去Fmoc保护基两次 (20min+5min)，5ml DMF洗4次，5ml DCM洗4次，Kaiser’s试剂检测。
(13)连接Ala(A)：DMF洗涤3次，分别加入3倍树脂摩尔量的 Fmoc-Ala-OH、HBTU、HOBt和6倍树脂摩尔量的DIEA，溶于10ml DMF中， 室温搅拌反应2h，DMF洗4次，加入20％哌啶DMF脱去Fmoc保护基两次 (20min+5min)，5ml DMF洗4次，5ml DCM洗4次，Kaiser’s试剂检测。
(14)连接棕榈酸(Pal)：DMF洗涤3次，分别加入6倍树脂摩尔量的棕 榈酸、HBTU、HOBt和10倍树脂摩尔量的DIEA，溶于10ml DMF中，室温搅 拌反应4h，5ml DMF洗4次，5mlDCM洗4次，Kaiser’s试剂检测。
(15)切割，解侧链保护基：产物加入250mg苯酚、0.5ml水、0.5ml苯甲 硫醚、9.0ml三氟乙酸，室温搅拌2.5h，过滤，N2吹去三氟乙酸，加入30ml冷 的无水乙醚，5000rpm离心5min，得到白色沉淀，用冷的无水乙醚重复洗涤3 次，真空干燥，得粗产物。
(16)粗产物使用反相制备液相色谱(RP-HPLC)纯化、收集目标峰流动相 溶液脱去乙腈后，冷冻干燥得到絮状或粉末状固体，即BH3模拟肽类似物纯品， 通过质谱和高效液相色谱分析进行结构确证。
以上述方法，得到的27个BH3模拟肽类似物的质谱数据和HPLC纯度分析 数据见表1。
表1 BH3模拟肽类似物的质谱数据和HPLC纯度分析数据
实施例2：蛋白酪氨酸磷脂酶1B(PTP1B)抑制活性测定
本发明中采用MES缓冲液为反应体系，利用人源蛋白酪氨酸磷酸酶1B (PTP1B)，以对硝基苯磷酸二钠(pNPP)为特异性底物，选择先导化合物SM-6 作为阳性对照、以DMSO为阴性对照，建立了基于酶反应速率的96孔微板为载 体的筛选模型，通过酶学方法寻找PTP1B抑制剂。
具体实施方法为：采用MES缓冲体系(25mM，pH6.5)，在96孔板内依 次加入10μLpNPP(77mM)、86μL MES缓冲液、4μL化合物(2mM)、100 μL PTP1B溶液(50nM)，反应总体积为200μL。每组3个平行，以DMSO为 阴性对照，原钒酸钠(2mM)为阳性对照，25℃下，在摇床上摇动1min，酶标 仪上每隔60s读数一次，动态测定5min，测其OD 405的变化(OD/min)。每 个孔的初始阶段反应速率呈线性相关，动力学曲线线性部分的斜率决定PTP1B 的反应速度，以速度表示酶活。所得数据用
表示，各组数据运用t检验分 析。化合物对PTP1B的抑制率计算公式：
抑制率(％)＝(vDMSO-v样本)/vDMSO×100％
其中，vDMSO、v样本分别表示阴性对照组和受试化合物的初始平均反应速率
本发明对模拟肽在10μmol/L浓度下进行PTP1B抑制率初筛，对初筛抑制率 高于70％的化合物进行IC50测定，抑制结果参见表2。
表2受试模拟肽类似物对PTP1B活性的抑制结果
*：初筛抑制率低于50％的化合物未进行IC50的测定。
采用GraphPad Prism软件进行统计学处理，绘制出抑制剂量效应曲线，见图 1，并计算得到模拟肽类似物scan-2、scan-3、scan-4、scan-5、scan-6、scan-7、 scan-8、scan-11、C13-SM6、C14-SM6、C16 diacid-SM6、C18-SM6、C18 diacid-SM6、 C20-SM6、C20 diacid-SM6、C22-SM6、C22 diacid-SM6和Lila-SM6的PTP1B 抑制中浓度IC50分别为91.6nmol/L、703.0nmol/L、580.9nmol/L、1208.0nmol/L、 56.5nmol/L、45.4nmol/L、63.7nmol/L、511.9nmol/L、835.4nmol/L、262.7nmol/L、 2875nmol/L、120.2nmol/L、384.6nmol/L、3887nmol/L、443.5nmol/L、337.9nmol/L、 199.6nmol/L、4345nmol/L。
试验结果表明：本发明的模拟肽类似物对蛋白质酪氨酸磷酸酯酶1B表现出 显著的抑制作用，能够作为优异的PTP1B抑制剂，并应用于以PTP1B为靶点的 抗糖尿病、抗肿瘤及抗阿尔兹海默症症药物的开发中，因此具有很好的开发前景。
以上实施例仅用以说明本发明的技术方案，而非对其进行限制；尽管参照前 述实施例对本发明进行了详细的说明，对于本领域的普通技术人员来说，依然可 以对前述实施例所记载的技术方案进行修改，或者对其中部分技术特征进行等同 替换；而这些修改或替换，并不使相应技术方案的本质脱离本发明所要求保护的 技术方案的精神和范围。
Claims (10)
1.一种抑制PTP1B活性的新型BH3模拟肽类似物，其特征在于，所述新型BH3模拟肽类似物的结构式如下：
其中，R1为长链羧酸，R2为COOH，R3为不同碳链长度的羧酸或多羧酸。
2.一种PTP1B多肽抑制剂BimBH3-12-G9A，其特征在于，所述PTP1B多肽抑制剂BimBH3-12-G9A的结构式如下：
3.根据权利要求2所述的PTP1B多肽抑制剂BimBH3-12-G9A，其特征在于，所述PTP1B多肽抑制剂BimBH3-12-G9A的制备方法包括以下步骤：
(1)室温下，将Fmoc-Phe-Wang树脂置于手动多肽固相合成器中，用二氯甲烷、二甲基甲酰胺活化；
(2)加入哌啶/二甲基甲酰胺混合液脱除Fmoc保护基；
(3)加入3-4倍树脂摩尔量的N-Fmoc保护氨基酸或羧酸、HOBT、HBTU以及5-6倍树脂摩尔量的DIEA，室温振荡反应2～4h；
(4)重复步骤(2)和(3)，直至完成整个模拟肽序列的合成；
(5)将步骤(4)的产物中加入裂解液，室温搅拌，过滤，加入无水乙醚析出固体后，经洗涤、真空干燥得模拟肽类似物粗产物；
(6)所述肽类似物粗产物使用反相制备液相色谱纯化，收集目标峰流动相溶液脱去乙腈后，冷冻干燥得到絮状或粉末状固体，即得PTP1B多肽抑制剂BimBH3-12-G9A纯品。
4.根据权利要求3所述的PTP1B多肽抑制剂BimBH3-12-G9A，其特征在于，所述裂解液包括苯酚、水、苯甲硫醚和三氟乙酸。
5.根据权利要求3所述的PTP1B多肽抑制剂BimBH3-12-G9A，其特征在于，所述步骤(5)中过滤后鼓吹N2去除多余的三氟乙酸。
6.以权利要求2-5任一项所述的PTP1B多肽抑制剂BimBH3-12-G9A为活性成分的药物或药物组合物，其特征在于，所述药物或药物组合物包括任一所述PTP1B多肽抑制剂BimBH3-12-G9A和一种或多种药学上可接受的载体或赋型剂。
7.权利要求2-5任一项所述的PTP1B多肽抑制剂BimBH3-12-G9A在制备用于抑制PTP1B活性的抑制剂中的应用。
8.权利要求2-5任一项所述的PTP1B多肽抑制剂BimBH3-12-G9A在制备用于预防或治疗以PTP1B为靶点的疾病的药物中的应用。
9.根据权利要求8所述的应用，其特征在于：所述疾病包括糖尿病、癌症和阿尔兹海默症。
10.根据权利要求8所述的应用，其特征在于：以PTP1B多肽抑制剂BimBH3-12-G9A为活性成分的药物或药物组合物的给药方式为口服或注射。
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