WO2011147253A1 - 预防和治疗糖尿病以及脂代谢紊乱的多肽 - Google Patents

预防和治疗糖尿病以及脂代谢紊乱的多肽 Download PDF

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WO2011147253A1
WO2011147253A1 PCT/CN2011/073798 CN2011073798W WO2011147253A1 WO 2011147253 A1 WO2011147253 A1 WO 2011147253A1 CN 2011073798 W CN2011073798 W CN 2011073798W WO 2011147253 A1 WO2011147253 A1 WO 2011147253A1
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diabetes
polypeptide
polypeptides
preventing
peptide
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French (fr)
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陈正望
杜仲夏
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JIANGSU WY-KINGT BIOSCIENCE Co Ltd
Huazhong University of Science and Technology
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JIANGSU WY-KINGT BIOSCIENCE Co Ltd
Huazhong University of Science and Technology
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/55—Protease inhibitors
    • A61K38/56—Protease inhibitors from plants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

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  • the present invention belongs to the field of biomedicine and relates to a medicament for preventing and treating diseases of diabetes and lipid metabolism disorders.
  • Diabetes is caused by genetic factors, immune dysfunction, microbial infections and their toxins, free radical toxins, mental factors and other pathogenic factors that cause islet dysfunction, insulin resistance (IR), etc.
  • IR insulin resistance
  • a series of metabolic disorders such as sugar, protein, fat, water and electrolytes. Diabetes has become the third largest "health killer" in humans following cancer, cardiovascular and cerebrovascular diseases. As the economy develops, obesity increases, and the human structure ages, the incidence of diabetes continues to grow.
  • WH ⁇ World Health Organization
  • insulin-dependent diabetes mellitus also known as type I
  • NIDDM noninsulin-dependent diabetes mellitus
  • Type II diabetes and other types of diabetes.
  • Type I patients often develop from childhood, also known as juvenile onset, which is caused by insufficient secretion of endogenous insulin and requires insulin therapy.
  • Type II patients have more onset after the age of 40, sometimes called the onset of the disease, the patient's hyperglycemia is mainly due to insulin signaling pathway barrier, insulin stimulates the ability of cells to take up glucose. Due to the complex etiology of diabetes, the pathogenesis is not completely clear, which brings great difficulties to treatment.
  • insulin is a water-soluble polypeptide, it is easily degraded by enzymes in the gastrointestinal tract, and thus is not suitable for oral administration;
  • Infusion therapy requires daily subcutaneous injection of insulin. Long-term frequent injection not only causes pain to the patient, but also may cause various adverse reactions such as subcutaneous fat contracture. In addition, long-term administration of insulin has the risk of causing hypoglycemia.
  • the object of the present invention is to provide a polypeptide for preventing and treating diabetes and a disorder of lipid metabolism and a preparation method thereof.
  • the polypeptide for preventing and treating diabetes and lipid metabolism disorder provided by the present invention has the following sequence
  • Sequence 1 ASCNGVCSPFEMPPCGSSACRCIPVGLVVGYCRHPSG Sequence 2: ISCNGVCSPFDIPPCGTPLCRCIPAGLFVGKCRHPYG
  • sequence 4 VSCNGVCSPFEMPPCGSSACRCIPYGLVVGNCRHPSG
  • the polypeptides provided by the present invention are useful for the prevention and treatment of diabetes and disorders of lipid metabolism disorders.
  • a medicament for preventing and treating diabetes and a disorder of a lipid metabolism can be prepared by using the polypeptide of the present invention as an active ingredient and a pharmaceutically acceptable carrier.
  • the peas (soybean) or the pressed soybean meal were soaked in 0.5 M acetic acid overnight, beaten, and the slurry was frozen and centrifuged. The supernatant was centrifuged with alginic acid, then eluted with 0.2 M hydrochloric acid, and the adsorption and elution operations were repeated 3 times. Desiccation is carried out for salting out, and the product after salting out is desalted by G-25 column. The desalted liquid is filtered through G-50 column, the filtrate is freeze-dried and concentrated, separated by HPLC, and different separation peak components are taken for pharmacodynamics. In the experiment, the peak component with hypoglycemic effect was finally selected for protein sequencing.
  • Peptide 1 peak 3) ASCNGVCSPFEMPPCGSSACRCIPVGLVVGYCRHPSG ( 37 )
  • Peptide 2 peak 4) ISCNGVCSPFDIPPCGTPLCRCIPAGLFVGKCRHPYG ( 37)
  • Peptide 3 peak 5) VSCNGVCSPFDIPPCGTPLCRCIPYGLFVGNCRHPYG (37)
  • Peptide 4 peak 7) VSCNGVCSPFEMPPCGSSACRCIPYGLVVGNCRHPSG (37) where A-alanine, C- Cysteine, D-aspartic acid, E-glutamic acid, F-phenylalanine, G-glycine, H-histidine, I-isoleucine, K-lysine, L- Leucine, M-methionine, N-asparagine, P-valine, R-arginine, S-serine, T-threonine, V-valine, Y-tyrosine
  • the four compounds are all white in appearance and are easily soluble in polar solvents such as water. They are stable to heat and resistant to protease hydrolysis.
  • mice The four polypeptides provided by the present invention were prepared by using physiological saline to prepare an oral liquid having a concentration of 2 mg/ml, which was used for experimental intragastric administration.
  • mice The animals in this experiment were all BABC mice, 10 in each group, randomized.
  • Type II diabetes 100 mg/kg - sub-dose injection of streptozotocin I (STZ), and fed with high-sugar and high-fat words to establish type II diabetes Mouse animal model.
  • Diabetic mice were randomly divided into a peptide gavage group, a metformin (positive control) group, a model control group, and a blank control group, with 10 rats in each group.
  • the drug was administered intragastrically every other day for 4 weeks, and the dose was 20 ug/g, and the blood glucose of the mice was determined weekly. The results are shown in Table 1.
  • Table 1 Changes in blood glucose in mice
  • Model control group 8.6 ⁇ 0.9 10.3 ⁇ 0 ⁇ 3 11.1 ⁇ 0 ⁇ 8 11.1 ⁇ 0 ⁇ 5
  • hypoglycemic effects of the four peptides are hyperglycemic and therefore safer.
  • mice after the above glucose tolerance test were taken from the eyeballs, and then sacrificed, and the serum was subjected to four tests of blood lipids.
  • the results showed that after administration, the total cholesterol in the peptide group and the metformin group was smaller than that in the model group, but there was no significant difference (P>0.05).
  • the triglyceride level in the peptide group and the metformin group was significantly lower than that in the model group (P>0.05). ⁇ 0.05)
  • Table 3 Changes in total cholesterol and triglycerides in BABC mice after administration
  • the rat pancreatic ⁇ cells were isolated, primary cultured, and the polypeptide of the present invention was added to the culture medium. The results showed that the cells to which the polypeptide was added grew vigorously, and the survival time was four days longer than that of the control cells without the polypeptide, as shown in Fig. 4. It is indicated that the polypeptide of the present invention has a protective effect on pancreatic ⁇ cells, and is suitable for administration to diabetic patients.
  • the four polypeptides provided by the present invention are indeed a safe and effective hypoglycemic and lipid-lowering drug, and the four polypeptides are equivalent in efficacy. Due to its resistance to enzymatic hydrolysis, it is suitable for oral preparation and can be used for oral administration. The hypoglycemic effect is obvious. The hypoglycemic effect occurs on the basis of hyperglycemia. It depends on glucose to lower the concentration of high blood sugar and does not cause hypoglycemia. It has good safety and has a certain protective effect on pancreatic ⁇ cells.
  • the polypeptide of the present invention can be used as a medicament for the treatment and prevention of diseases of diabetes and disorders of lipid metabolism.
  • Figure 1 is an extraction process diagram of four polypeptides
  • Figure 2 is a HPLC chromatogram in the process flow of the present invention.
  • Figure 4 Isolation of pancreatic ⁇ -cells from rats, primary culture, addition of polypeptides to the medium, protection of pancreatic ⁇ -cells by the peptides (arrows represent viable beta cells), and the results showed that the cells added with the polypeptide of the present invention grew vigorously and survived. The time was up to four days longer than the control cells without the addition of the polypeptide.
  • the peas were soaked in 0.5 M acetic acid overnight, beaten, and the slurry was frozen and centrifuged. The supernatant was centrifuged with alginic acid, then eluted with 0.2 M hydrochloric acid, and the adsorption and elution operations were repeated three times. The eluate was subjected to salting out and salting out. After the product is desalted by G-25 column, the desalted liquid is filtered through G-50 column, the filtrate is freeze-dried and concentrated, and separated by HPLC (see Figure 2), taking peak 3, peak 4, peak 5, peak 7 The substance, that is, the polypeptide of the present invention. The obtained polypeptide was subjected to protein sequencing, and the results were as follows:
  • Peptide 1 peak 3) ASCNGVCSPFEMPPCGSSACRCIPVGLVVGYCRHPSG ( 37 )
  • Peptide 2 peak 4) ISCNGVCSPFDIPPCGTPLCRCIPAGLFVGKCRHPYG ( 37)
  • Peptide 3 peak 5) VSCNGVCSPFDIPPCGTPLCRCIPYGLFVGNCRHPYG (37)
  • Peptide 4 peak 7) VSCNGVCSPFEMPPCGSSACRCIPYGLVVGNCRHPSG (37)

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Description

预防和治疗糖尿病以及脂代谢紊乱的多肽
【技术领域】
本发明属于生物医药领域， 涉及预防和治疗糖尿病和脂代谢紊乱疾病的药 物。
【技术背景】
糖尿病 （diabetes)是由遗传因素、 免疫功能紊乱、 微生物感染及其毒素、 自由基毒素、 精神因素等等各种致病因子作用于机体导致胰岛功能减退、 胰岛 素抵抗 (Insulin Resistance, IR)等而引发的糖、 蛋白质、 脂肪、 水和电解质等一 系列代谢紊乱综合征。 糖尿病已经成为人类继癌症、 心脑血管疾病之后的第三 大 "健康杀手"。 随着经济发展， 肥胖增多以及人类结构的老年化， 糖尿病的发 病率持续增长。
1980年， 世界卫生组织（world health organization,WH〇）将糖尿病分为： 胰岛素依赖性糖尿病 （insulin-dependent diabetes mellitusJDDM,又称 I型）， 非胰岛素依赖性糖尿病 （noninsulin-dependent diabetes mellitus,NIDDM,又称
II型） 及其他类型糖尿病。 I型患者常起病于幼年， 又称为少年发病型， 是由 内源性胰岛素分泌不足引起，多需要胰岛素治疗。 II型患者多起病于 40岁以后， 有时称陈年发病型， 患者的高血糖症主要是由于胰岛素信号通路障碍， 胰岛素 刺激细胞摄取葡萄糖的能力下降。 由于糖尿病病因复杂， 发病机制还不完全清 楚， 给治疗带来了极大的困难。
目前治疗糖尿病以注射给予胰岛素为主， 而由于胰岛素是一种水溶性多肽， 易于被胃肠道内的酶降解， 因此不适宜于口服给药； 而且糖尿病患者实施胰岛 素治疗需要终生每日皮下注射胰岛素， 长期频繁注射不但给患者带来痛苦， 还 可能产生皮下脂肪蒌缩等多种不良反应。 另外长期给予胰岛素治疗有引发低血 糖症的危险。
【发明内容】
本发明的任务是提供一种预防和治疗糖尿病以及脂代谢紊乱的多肽及其制 备方法。
实现本发明的技术方案是：
本发明提供的这种预防和治疗糖尿病以及脂代谢紊乱的多肽具有以下序列
1至 4中任一项所示的氨基酸序列：
序列 1 : ASCNGVCSPFEMPPCGSSACRCIPVGLVVGYCRHPSG 序列 2: ISCNGVCSPFDIPPCGTPLCRCIPAGLFVGKCRHPYG
序列 3: VSCNGVCSPFDIPPCGTPLCRCIPYGLFVGNCRHPYG
序列 4: VSCNGVCSPFEMPPCGSSACRCIPYGLVVGNCRHPSG 本发明提供的多肽可用于预防和治疗糖尿病以及脂代谢紊乱疾病。 以本发 明多肽为活性成分和药学上可接受的载体， 可制备用于预防和治疗糖尿病以及 脂代谢紊乱疾病的药物。
本发明多肽提取工艺：
豌豆（大豆）或搾油后的豆粕， 经 0.5M醋酸浸泡过夜， 打浆， 浆液冷冻离 心， 离心上清液用海藻酸吸附， 然后用 0.2M盐酸洗脱， 重复吸附和洗脱操作 3 遍，洗脱液进行盐析，盐析后的产品经过 G-25柱脱盐，脱盐后的液体经过 G-50 柱过滤， 滤液冷冻干燥浓缩， 用 HPLC进行分离， 取不同的分离峰组分进行药 效学实验，最终选择有降糖作用的峰组分进行蛋白测序。提取工艺流程图见图 1。 产率： 11^大豆→打浆→离心→海藻酸吸附→盐析（109， 1 %)→脱盐（6g， 0.6%) →G-50柱过滤 （3g， 0.3%) →HPLC (500mg， 0.05%)
多肽的鉴定：
1 . 收集 HPLC中各分离峰的分离液 （见图 2) 分别进行药效学试验， 结果 发现峰 3， 峰 4， 峰 5， 峰 7中的物质有降糖效果， 然后分别将这四种物质进行 蛋白测序， 测序结果为：
多肽 1 (峰 3) ASCNGVCSPFEMPPCGSSACRCIPVGLVVGYCRHPSG ( 37 ) 多肽 2 (峰 4) ISCNGVCSPFDIPPCGTPLCRCIPAGLFVGKCRHPYG ( 37) 多肽 3 (峰 5) VSCNGVCSPFDIPPCGTPLCRCIPYGLFVGNCRHPYG (37) 多肽 4 (峰 7) VSCNGVCSPFEMPPCGSSACRCIPYGLVVGNCRHPSG (37) 其中， A-丙氨酸、 C-半胱氨酸、 D-天冬氨酸、 E-谷氨酸、 F-苯丙氨酸、 G- 甘氨酸、 H-组氨酸、 I-异亮氨酸、 K-赖氨酸、 L-亮氨酸、 M-甲硫氨酸、 N-天冬 酰胺、 P-脯氨酸、 R-精氨酸、 S-丝氨酸、 T-苏氨酸、 V-缬氨酸、 Y-酪氨酸
2. 物理性状
该四种化合物外观均为白色粉末， 极易溶解于水等极性溶剂， 对热稳定， 耐蛋白酶水解。
3. 命名
本发明专利申请将该四种多肽一起命名为 legaglycins, 中文名： 胰怡素。 药效学实验资料
1. 实验用药及实验动物
实验用药： 取本发明提供的四种多肽， 均用生理盐水分别配制成浓度为 2mg/ml的口服液， 供实验灌胃使用。 实验动物： 本实验中的动物均为 BABC小鼠， 每组 10只， 随机分组。
2. 实验方法及结果
1) 治疗 II型糖尿病效果实验 建立 II型糖尿病小鼠动物模型： 100mg/kg —次性大剂量注射链脲佐菌 I (STZ), 并以高糖高脂词料喂养， 建立 II型糖尿病小鼠动物模型。 将糖尿病小鼠随机分为多肽灌胃组、 二甲双胍（阳性对照）组、 模型对照 和空白对照组，每组 10只。 隔日灌胃给药， 持续 4周， 给药量为 20ug/g， 每周 定小鼠的血糖。 结果见表 1。 表 1: 小鼠血糖变化情况
血糖值 (mmol. L-1)
1周 2周 3周 4周 多肽 1 7.1±0.6 7.3±0· 5 7.0±0.4 6·9±0· 3
多肽 2 7·2±0· 2 7·4±0· 6 7·2±0· 4 7.0±0.2
多肽 3 7·1±0· 5 7.3±0· 3 7.0±0.2 6·9±0· 2
多肽 4 7·2±0· 3 7·4±0· 5 7.2±0· 4 7.0±0· 3
二甲双胍 7·2±0· 3 7·4±0· 4 7·3±0· 5 7·2±0· 4
空白对照组 5.6±0.4 5.9±0· 2 5.7±0· 3 5.4±0· 4
模型对照组 8.6±0.9 10.3±0· 3 11.1±0· 8 11.1±0· 5
结论： 四种多肽具有明显的 π型糖尿病治疗效果， 作用相当于或略优于二甲 胍。
2) 口服后的耐糖量测试 （OGTT) 结果 降糖实验中， 在末次给药 lh 后， 灌胃给予各小鼠 2.5g/kg 葡萄糖， 0h，0.5h，2h测定小鼠血糖值。 结果见表 2。 表 2 多肽口服后耐糖量 （0GTT) 实验结果
血糖值 (mmol. L _1)
Oh 0.5h 2h
多肽 1 6·3±0· 3 14.1±0· 2 6.5±0· 4
多肽 2 6·4±0· 2 14.6±0· 3 6.7±0· 3
多肽 3 6·3±0· 4 14.0±0· 4 6.4±0· 4 多肽 4 6.3±0.2 14.1±0.2 6.5±0.2
二甲双胍 6.5±0.4 14.9±0.2 7.4±0.1
模型对照组 9.9 ±0.6 22.1±1· 5 11.3±0· 7
结论： 四种多肽的降糖作用具有高血糖依赖性， 因此具有更高的安全性。
3) 耐胃蛋白酶和胰蛋白酶酶解试验
将四种多肽样品用胃肠道酶水解 12h后， HPLC检其降解情况。 结果表明这 些能抗胃肠道酶水解， 结果见图 3， HPLC图中未见任何被水解后的小片段， 说 明多肽未被胃蛋白酶水解。 结论： 四种多肽能耐胃蛋白水解， 可开发为口服制剂。
4) 降脂作用
将上述糖耐量试验结束后的小鼠摘眼球取血， 然后处死， 血清进行血脂四 项检测。 结果显示： 给药后， 多肽组和二甲双胍组的总胆固醇均小于模型组， 但并无明显差异 （P>0.05); 而多肽组与二甲双胍组的甘油三酯水平均显著低于 模型组 （P〈0.05) 结果见表 3。 表 3 给药后 BABC小鼠的总胆固醇及甘油三酯变化情况
总胆固醇 （mg/dl) 甘油三酯 （mg/dl)
多肽 1 98±0.2 45±0.3
多肽 2 99±0.3 45±0.2
多肽 3 98±0.1 44±0.2
多肽 4 97±0.3 44±0.3
二甲双胍 100±0.2 50±0.4
模型对照组 118±0.4 1223±0.2
结论： 四种多肽具有显著降低血中甘油三酯水平的能力， 可开发为一种调脂药 物。
5) 安全性评价
对给药后试验动物进行长达一年的观察， 未发现药物不良反应， 未见药物 副作用产生， 无毒性、 致癌、 致畸形， 致变态反应， 证明该四种多肽药用的安 全性。 6) 对胰岛细胞的保护作用
分离大鼠的胰腺 β细胞， 原代培养， 培养基中加入本发明多肽， 结果表明： 加入多肽的细胞生长旺盛，存活时间比未加多肽的对照组细胞长达四天，见图 4。 说明本发明多肽对胰腺 β细胞具有保护作用， 适宜糖尿病患者用药。
7) 改善和促进胰腺 β细胞的分泌功能 通过膜片钳实验， 我们发现多肽能抑制胰腺 β细胞的 ΚΑΤΡ通道， 同胰岛素一 样诱导细胞外钙内流， 从而改善和促进胰腺 β细胞的分泌功能， 结果见图 5。膜 片钳实验证实本发明多肽与 Insulin—样诱导细胞外钙内流从而促进胰腺 β细 胞分泌胰岛素。 此结果说明这些多肽在体内对胰腺细胞的生长繁殖和生理功能 的恢复起到良好的促进作用， 从而使失去正常功能的胰腺得以修复。
综合以上药效结果， 说明本发明提供的这四种多肽确实是一种安全有效的 降糖和调脂药物， 而且这四种多肽的药效相当。 由于其耐酶解， 适宜开发为口 服制剂， 可用于口服给药治疗， 降糖效果明显， 其降糖作用是在高血糖基础上 发生， 是依赖葡萄糖而降低高血糖浓度， 不会导致低血糖， 安全性好， 而且对 胰腺 β细胞有一定的保护作用。 另外， 药理实验还发现， 该系列多肽具有明显 降低血中甘油三酯作用， 具有调节血脂的作用。 因此， 本发明多肽可作为治疗 和预防糖尿病以及脂代谢紊乱疾病的疾病的药物。
【附图说明】 图 1 四种多肽的提取工艺图；
图 2 本发明工艺流程中的 HPLC图谱；
图 3 多肽经胃蛋白酶水解后的 HPLC图谱；
图 4 分离大鼠的胰腺 β细胞， 原代培养， 培养基中加入多肽， 多肽对胰腺 β细胞的保护作用 （箭头代表存活的 β细胞）， 结果表明： 加入本发明多肽的细 胞生长旺盛， 存活时间比未加多肽的对照组细胞长达四天。
图 5 本发明多肽的膜片钳实验。 【具体实施方式】
实施例 1
本发明多肽的制备
将豌豆经 0.5M醋酸浸泡过夜， 打浆， 浆液冷冻离心， 离心上清液用海藻酸 吸附， 然后用 0.2M盐酸洗脱， 重复吸附和洗脱操作 3遍， 洗脱液进行盐析， 盐 析后的产品经过 G-25柱脱盐， 脱盐后的液体经过 G-50柱过滤， 滤液冷冻干燥 浓缩， 用 HPLC进行分离 （见图 2)， 取峰 3， 峰 4， 峰 5， 峰 7中的物质， 即 得本发明多肽。 对得到的多肽进行蛋白测序， 结果如下：
多肽 1 (峰 3) ASCNGVCSPFEMPPCGSSACRCIPVGLVVGYCRHPSG ( 37 ) 多肽 2 (峰 4) ISCNGVCSPFDIPPCGTPLCRCIPAGLFVGKCRHPYG ( 37) 多肽 3 (峰 5) VSCNGVCSPFDIPPCGTPLCRCIPYGLFVGNCRHPYG (37) 多肽 4 (峰 7) VSCNGVCSPFEMPPCGSSACRCIPYGLVVGNCRHPSG (37)

Claims

权利 要求
1. 用于预防和 /或治疗糖尿病和 /或脂代谢紊乱的多肽， 其特征在于， 具 有以下序列 1至 4中任一项所示的氨基酸序列：
序列 1 : ASCNGVCSPFEMPPCGSSACRCIPVGLVVGYCRHPSG
序列 2: ISCNGVCSPFDIPPCGTPLCRCIPAGLFVGKCRHPYG
序列 3: VSCNGVCSPFDIPPCGTPLCRCIPYGLFVGNCRHPYG
序列 4: VSCNGVCSPFEMPPCGSSACRCIPYGLVVGNCRHPSG
2. 权利要求 1所述的多肽在制备用于预防和 /或治疗糖尿病和 /或脂代谢 紊乱的药物中的应用。
3 . 一种用于预防和 /或治疗糖尿病和 /或脂代谢紊乱的药剂， 其特征在 于含有有效量的权利要求 1所述的多肽和药学上可接受的载体。
PCT/CN2011/073798 2010-05-26 2011-05-09 预防和治疗糖尿病以及脂代谢紊乱的多肽 Ceased WO2011147253A1 (zh)

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