CN109456395A - 一种降糖肽及其应用 - Google Patents
一种降糖肽及其应用 Download PDFInfo
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- CN109456395A CN109456395A CN201811572732.2A CN201811572732A CN109456395A CN 109456395 A CN109456395 A CN 109456395A CN 201811572732 A CN201811572732 A CN 201811572732A CN 109456395 A CN109456395 A CN 109456395A
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- incretin peptide
- peptide
- incretin
- modified peptides
- acid
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/415—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from plants
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/17—Amino acids, peptides or proteins
- A23L33/18—Peptides; Protein hydrolysates
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/17—Amino acids, peptides or proteins
- A23L33/185—Vegetable proteins
-
- 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
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Diabetes (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Molecular Biology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Polymers & Plastics (AREA)
- Food Science & Technology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Nutrition Science (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Mycology (AREA)
- Public Health (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Botany (AREA)
- Gastroenterology & Hepatology (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明提供了一种降糖肽，具有如SEQ ID NO：1所示的氨基酸序列ADWGGPLPH。本发明还提供了所述降糖肽的修饰肽，在降糖肽的N端、C端或中间残基上连接化学基团、氨基酸、多肽、蛋白质或PEG。本发明所述降糖肽，能够促进高糖条件下平滑肌细胞的糖吸收，能改善糖尿病小鼠的糖耐量并且增强小鼠的血糖利用能力，显著地降低血清总胆固醇和血清总甘油三酯，显著地改善SOD水平并降低MDA水平，修复糖尿病小鼠肝脏氧化损伤，抑制糖尿病小鼠血浆中炎症因子的产生，可以抗代谢综合症，可用于制备治疗和/或预防糖尿病或高血脂症的药物或保健品。
Description
技术领域
本发明属于生物技术领域，具体涉及一种降糖肽及其应用。
背景技术
糖尿病（Diabetes mellitus，DM）是以胰岛素相对或绝对不足为特征、高血糖症为主要症状的代谢混乱疾病，胰岛素分泌不足或相关功能受阻进而引发血糖升高，导致机体代谢紊乱，最终影响正常生理功能并引起并发症如动脉粥样硬化，白内障及胰腺炎等。常见的糖尿病分为Ⅰ型糖尿病和Ⅱ型糖尿病。传统抗糖尿病药物存在诸多不足:最常见的治疗方法为注射胰岛素，但其给药不便，且注射后易引发低血糖；二甲双胍类药物服用后不良反应严重。
发明内容
本发明提供一种能够口服、安全性好、具有较好降糖效果的降糖肽。
本发明的另一目的是提供所述降糖肽的应用。
本发明的技术方案如下：
一种降糖肽，具有如SEQ ID NO：1 所示的氨基酸序列，具体为 Ala-Asp-Trp-Gly-Gly-Pro-Leu-Pro-His。
可采用现有技术领域常规方法对降糖肽进行修饰。
对于蛋白质和肽类药物，在多数情况下，机体内的氨肽酶及羧肽酶很容易从常见的直链肽的两端进行逐步的切割分解，使直链肽被降解。多肽修饰是改变肽链主链结构和侧链基团的重要手段，已有大量文献表明经过修饰后的多肽药物可以显著降低免疫原性、减少毒副作用、增加水溶性、延长体内作用时间、改变其生物分布状况等等，明显改善药物的疗效。
多肽类药物常用修饰方法包括主链末端的修饰、中间残基的修饰、环化、氨基酸替换、糖基化修饰及PEG 修饰等。
多肽类药物常用的主链末端修饰方法是N端甲酰化、乙酰化作用和C 端的酰胺化作用，分别对肽链两端氨基和羧基进行保护，使多肽不会很快地被相应的多肽蛋白酶降解。目前这一技术已经广泛应用于多肽的化学合成中。N 端乙酰化通常是在固相合成多肽反应的整个肽链组合完毕后，加入乙酸酐使其乙酰化。C 端的酰胺化则是通过选择裂解产物为酰胺的树脂或者选择不同裂解方式来完成。主链末端连接不同长度的脂肪酸、主链C 端或N端的PEG 修饰及糖基化修饰，其基本原理都是增加多肽分子的相对分子量和空间位阻，提高其对多肽水解酶的稳定性，减少肾小球的滤过作用。替换肽链中的某几个氨基酸是另一种推迟酶降解使多肽药物的半衰期延长的方式，替换对象通常为肽链中的易酶解的氨基酸。此外，将L 型氨基酸替换为D 型非天然氨基酸也是氨基酸替换的一种常规方法。
本发明提供了一种降糖肽的修饰肽，其特征在于对降糖肽进行修饰，在降糖肽的N端、C 端或中间残基上连接化学基团、氨基酸、多肽、蛋白质或PEG。
本发明所述降糖肽的修饰肽具体优选为：对降糖肽的N 端进行甲酰化或乙酰化，或者在N端连接脂肪酸、肼基烟酰胺、二乙烯三胺五乙酸、肉豆蔻酸、十六酸或琥珀酰胺或PEG ；或者对降糖肽C 端进行酰胺化、或在C 端连有p-硝基苯胺、7-氨基-4-甲基香豆素；或者对降糖肽中间残基进行糖基化、磷酸化、甲基化、乙酰化、硝基化、磺酸化或者连接PEG 修饰或者降糖肽中间残基偶联蛋白质，其中：糖基化修饰最常用的为N- 糖基化和O-糖基化。
甲基化修饰肽包括侧链甲基化修饰肽和N 端甲基化修饰肽。
N端甲基化优选在降糖肽氨基酸序列中的一个或多个氨基酸的N 端甲基化。
PEG 修饰优选PEG 分子量为2000-10000。
本发明还提供了一种降糖肽的修饰肽，通过降糖肽的N 端和C 端首尾连接成环。
本发明还提供了一种降糖肽的修饰肽，降糖肽或上述修饰肽氨基酸序列中的一种或多种氨基酸替换成相应的氨基酸衍生物或特殊氨基酸。
本发明所述的降糖肽，国内外尚无相关报道。作为一种小肽，完全不同于已经上市的三大抗糖尿病肽类药物——普兰林肽、艾塞那肽和利拉鲁肽。降糖肽分子短小，可口服给药，规避消化。本发明选用STZ诱导糖尿病小鼠模型C57BL/6小鼠研究降糖肽连续给药对小鼠的影响，观察降糖肽对小鼠的体重、空腹血糖、血脂、葡萄糖耐量、肝超氧化物歧化酶（Superoxide dismutase，SOD）和肝丙二醛（malonaldehyde，MDA）的影响。
口服葡萄糖耐量试验（Oral glucose tolerance test，OGTT）是糖尿病实验室检查和糖尿病诊断的重要标准，可以根据OGTT 的结果计算相应的血糖曲线下面积（AUC）值。血糖AUC 值越低，说明实验动物对血糖的利用程度越高。本发明对小鼠进行了OGTT，结果提示本发明所述降糖肽能部分地改善小鼠的糖耐量并且部分地增强小鼠的血糖利用能力。降糖肽能显著地改善小鼠的空腹血糖和糖耐量，显著地降低血清总胆固醇和血清总甘油三酯，显著地改善SOD 水平并降低MDA 水平，保护机体细胞对抗氧自由基的氧化，说明降糖肽具有降糖，降脂功能和抗氧化功能，可以抗代谢综合症。
本发明所述的降糖肽作为一种结构清楚的小肽药物，其氨基酸序列决定了它可以规避胃肠道消化，从而有助于开展较为充分的药效学研究，有利于开发成口服药物。
本发明提供了上述降糖肽在制备治疗和/ 或预防糖尿病或高血脂症药物或保健品中的应用。特别是在在制备治疗和/ 或预防Ⅱ型糖尿病或高血脂症药物或保健品中的应用。
本发明提供了上述降糖肽的修饰肽在制备治疗和/ 或预防糖尿病或高血脂症药物或保健品中的应用。特别是在在制备治疗和/ 或预防Ⅱ型糖尿病或高血脂症药物或保健品中的应用。
本发明所述的药物，可以包含降糖肽或降糖肽的修饰肽以及一种或多种可药用的稀释剂或载体。
本发明所述式降糖肽或降糖肽的修饰肽可以以单一药物的形式被给药或可以与其它药物联合给药。
本发明的降糖肽或降糖肽的修饰肽可以成盐，包括与各种无机或有机酸盐如盐酸盐、氢溴酸盐、磷酸盐、硫酸盐、柠檬酸盐、乳酸盐、酒石酸盐、马来酸盐、延胡索酸盐、扁桃酸盐和草酸盐；各种无机或有机碱盐如氢氧化钠、三羟甲基氨基甲烷和N-甲基-葡萄糖胺成盐。
本发明的降糖肽或降糖肽的修饰肽可以单独使用或以药物组合物的形式使用。药物组合物包括作为活性成分的本发明的降糖肽或降糖肽的修饰肽或其可药用盐及可药用载体。较佳的，本发明的药物组合物有0.1-99.9% 重量百分比的作为活性成分的降糖肽或降糖肽的修饰肽或其可药用盐。“可药用载体”不会破坏本发明的化合物或其可药用盐的药学活性，同时其有效用量，即能够其药物载体作用是的用量对人体无毒。
“可药用载体”包括但不限于：离子交换材料、氧化铝、硬脂酸铝、卵磷脂、自乳化药物传递系统（SEDDS）如d-维生素E 聚乙二醇1000 琥珀酸酯、吐温或其他类似聚合介质等药物制剂用的表面活性剂、血清蛋白如人血清白蛋白、缓冲物质如磷酸盐、氨基乙酸、山梨酸、山梨酸钾、饱和植物脂肪酸部分甘油酯混合、水、盐、电解质如硫酸盐精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、硅胶、硅酸镁等。聚乙烯吡咯酮、纤维素物质、聚乙烯醇、羧甲基纤维素钠、聚丙烯酸酯、乙烯- 聚氧乙烯- 嵌段聚合物和羊毛脂、环糊精如α-、β-、γ- 环糊精或其经化学修饰的衍生物如2- 和3- 羟丙基-β- 环糊精等羟烷基环糊精或其他可溶性衍生物等均可用于促进本发明的化合物、其药用盐或前药的药物传递。
其他可药用辅料如填充剂（如无水乳糖、淀粉、乳糖珠粒和葡萄糖）、粘合剂（如微晶纤维素）、崩解剂（如交联羧甲基淀粉钠、交联羧甲基纤维素钠、低取代羟丙基纤维素和交联PVP）、润滑剂（如硬脂酸镁）、吸收促进剂、香味剂、甜味剂、稀释剂、赋形剂、润湿剂、溶剂、增溶剂和着色剂等也可加入本发明的药物组合物中。
上述本发明的降糖肽或降糖肽的修饰肽或其可药用盐以及药物组合物可通过肠道或者非肠道途径给药。非肠道给药制剂包括注射剂、霜剂、软膏剂、贴剂、喷雾剂等。给药途径包括皮下、皮内、动脉内、静脉内、肌内、关节内、滑液内、胸骨内、鞘内、病灶内、颅内注射或输注，或者，口服、局部、直肠、经鼻、经颊、阴道、舌下、皮内、粘膜、气管、尿道给药，或者通过吸入气雾或植入蓄积或者针刺方式给药。
上述本发明的降糖肽或降糖肽的修饰肽或其可药用盐以及药物组合物的治疗有效量为0.001-100mg/kg/d 之间，可用于相关疾病的单一用药或联合用药治疗，为本领域技术人员能够理解的范围。
通过实验，发现来源于麦胚清蛋白的降糖肽（氨基酸序列如SEQ ID NO:1所示）能够规避胃肠道消化，促进高糖环境下平滑肌细胞的糖吸收作用，能改善糖尿病小鼠的糖耐量并且增强小鼠的血糖利用能力，降低血清总胆固醇和血清总甘油三酯，显著地改善SOD水平并降低MDA 水平，修复糖尿病小鼠肝脏氧化损伤，抑制糖尿病小鼠血浆中炎症因子的产生。肽分子既不在肝脏代谢又不在脂肪组织累积，能有效避免肝脏毒性和累积毒性。因此，该降糖肽可以用于制备治疗糖尿病的药物。
附图说明
图1为降糖肽经模拟胃肠道消化实验前后的液相图。
图2为不同浓度降糖肽对细胞中糖吸收的影响，横坐标表示组别，纵坐标表示葡萄糖含量（mmol/L），AOP-5、AOP-10、AOP-20、AOP-40分别表示添加了含5μM、10μM、20μM、40μM降糖肽高糖培养液的实验组。#：与HG组相比有显著差异（p<0.05）；##：与HG组相比有极显著差异（p<0.01）。
图3 降糖肽对小鼠葡萄糖耐量的影响, #表示与STZ诱导模型组相比有显著差异（p<0.05）；##表示与STZ诱导模型组相比有极显著差异（p<0.01），下同。
图4 降糖肽对糖尿病小鼠血清理化指标的影响，#：与STZ诱导模型组相比有显著差异（p<0.05）；##：与STZ诱导模型组相比有极显著差异（p<0.01），下同。
图5降糖肽对糖尿病小鼠肝脏抗氧化能力的影响。#：与STZ诱导模型组相比有显著差异（p<0.05）；##：与STZ诱导模型组相比有极显著差异（p<0.01）。
图6 降糖肽对糖尿病小鼠血清炎症因子的影响。#：与STZ诱导模型组相比有显著差异（p<0.05）；##：与STZ诱导模型组相比有极显著差异（p<0.01）。
具体实施方式
酶解麦胚清蛋白，提取到了氨基酸序列如SEQ ID NO:1所示的降糖肽。以下实施例采用金斯瑞生物科技有限公司合成的降糖肽进行实验。
实施例1 模拟胃肠道消化下降糖肽的稳定性
模拟胃肠道消化实验：准确称取降糖肽（氨基酸序列如SEQ ID NO:1所示）3mg，溶解于100ml去离子水中，用1mol/L盐酸调节溶液pH至2.0；加入胃蛋白酶0.12mg，搅拌后在37℃恒温摇床中孵育2h;样品在沸水浴中加热10min灭酶。然后用1mol/L氢氧化钠溶液调节溶液pH至7.5；加入胰蛋白酶0.12mg，适度搅拌后在37℃恒温摇床中孵育2h, 最后在沸水浴中加热10min灭酶。
用高效液相色谱检测经模拟胃肠道消化实验后的降糖肽（记为LY-1），以未经处理的降糖肽（记为LY-2）为对照。HPLC条件：色谱柱为C18柱(4.6*250mm，5μm)，流动相A为含0.1%三氟乙酸的乙腈溶液，流动相B为含0.1%三氟乙酸的超纯水；洗脱梯度0-15min,流动相A 15%-55%；15-25min，流动相A 55%-15%；检测波长220nm，流速0.8ml/min，进样量20ul。
结果：如图1所示，从HPLC结果可以发现，LY-1以及LY-2出峰时间没有区别，并且没有其他峰出现，因此可以确定序列如SEQ ID NO:1所示的降糖肽在模拟胃肠道代谢体系中并没有发生变化。
实施例2 平滑肌细胞葡萄糖消耗测试
取对数生长期的平滑肌细胞（VSMC），以8×104个/mL的细胞密度接种于96孔板中，接种体积为100μL/孔，待细胞贴壁生长后，弃去上清液。将VSMC细胞分为三组：第一组（空白组，缩写为NG），加入低糖培养液100 μL/孔；第二组（模型组，缩写为HG），加入高糖培养液，100μL/孔；第三组（实验组）设置4组不同条件，分别加入含5μM、10μM、20μM、40μM降糖肽（序列如SEQ ID NO:1所示）的高糖培养液，100 μL/孔；每个浓度设6个复孔。其中，低糖培养液是添加有10%血清的DMEM培养基（葡萄糖浓度为5mM），高糖培养液是添加有10%血清的DMEM培养基（葡萄糖浓度为25mM）。按上述方法加药后，将96孔板置培养箱继续孵育24 h、48h后，取上清液2μL，参照葡萄糖测定试剂盒说明书，测定各组细胞葡萄糖消耗量。
结果：由图2可以看出，与模型组（HG组）相比，实验组随着培养液中降糖肽浓度的增高，葡萄糖消耗量显著增加，说明降糖肽（序列如SEQ ID NO:1所示）对高糖条件下的平滑肌细胞葡萄糖消耗量有明显改善作用。
实施例3 降糖肽对糖尿病小鼠的影响
1.糖尿病小鼠建模方法
本段描述糖尿病小鼠建模方法。C57BL6雄性小鼠30只，每只体重20±2g，由无锡山禾制药公司提供。用普通饲料喂养1周以适应环境。之后，每组10只（分笼饲喂，5只/笼），将小鼠随机分为3组：正常对照组（标记为WT）、STZ诱导模型组（标记为STZ），实验组（标记为STZ+AOP）。STZ诱导模型组和实验组腹腔注射STZ（链脲佐菌素），50 mg/kg，STZ给药持续5天；正常对照组给予相同量的柠檬酸钠注射。STZ给药结束后7天，禁食12小时，尾端取血测试小鼠空腹血糖，发现STZ诱导模型组和实验组各小鼠血糖值均高于220 mg/dl，造模成功。
造模成功后，正常对照组、STZ诱导模型组和实验组均常规饲料喂养1周，然后采用降糖肽（序列如SEQ ID NO:1所示）进行干预。具体方法为：实验组每日腹腔注射20 mg/kg的降糖肽（AOP），其余各组每日腹腔注射相同剂量的生理盐水溶液，连续给药四周。药液注射前，均采用0.22μm滤膜过滤除菌。
2.腹腔葡萄糖耐量实验
方法：降糖肽连续给药四周后，对各组小鼠进行12小时的禁食不禁水处理，于第二天上午9点进行腹腔葡萄糖耐量实验，每只小鼠腹腔注射0.5g/kg葡萄糖，分别于0、15、30、45、60、90、120分钟进行尾静脉取血测定血糖。绘制葡萄糖耐量时间曲线，并做统计分析。
结果：结果如图3所示，与正常对照组相比，在注射葡萄糖后STZ诱导模型组小鼠的血糖急剧上升，表明其葡萄糖耐受明显受到损伤，实验组小鼠的葡萄糖耐受程度与STZ诱导模型组相比有显著性改善，表明该降糖肽具有改善糖尿病小鼠葡萄糖耐量的作用。
3.处死后糖尿病小鼠样品制备
方法：降糖肽连续给药四周后，各组实验小鼠处死，眼眶取血保存在EDTA浸润的1.5 mL离心管内，在室温下静置30分钟后冷冻离心取上清液冻存；部分肝脏和主动脉组织置于 4℃生理盐水中，洗净表面残留血液，加入预冷的生理盐水，高速匀浆，制备成 10％的组织匀浆；部分肝脏和主动脉组织浸没于10 %福尔马林溶液中固定；其余组织放入-80℃冰箱冻存。
4. 测定TG、TC、HDL-C、LDL-C
方法：取本实施例标题3中分离的血清，采用市售试剂盒测定血清TG（总甘油三酯）、TC（总胆固醇）、HDL-C（高密度脂蛋白胆固醇）、LDL-C（低密度脂蛋白胆固醇）。
结果：如图4，经过4周的降糖肽干预后，实验组小鼠血清中的TG、TC、LDL-C水平与STZ诱导模型组对比，均有了显著性的降低（P < 0.05），表明该降糖肽具有降低糖尿病小鼠高血脂的作用。
5.小鼠肝脏中SOD（超氧化物歧化酶）活力
方法：按南京建成生物工程研究所 SOD 测定试剂盒说明书，取10%肝脏匀浆进行测试。
结果：如图5所示，经过4周的降糖肽干预后，实验组小鼠肝脏中SOD活力水平与STZ诱导模型组对比，有了显著性的提高（P < 0.05），实验结果表明该降糖肽具有改善糖尿病小鼠抗氧化能力的作用。
6.小鼠肝脏中MDA（丙二醛）含量
方法：按南京建成生物工程研究所 MDA 测定试剂盒说明书，取10%肝脏匀浆检测MDA含量。
结果：如图5所示，经过4周的降糖肽干预后，实验组小鼠肝脏中的MDA含量与STZ诱导模型组对比，有了显著性的降低（P < 0.05），表明该降糖肽具有抑制糖尿病小鼠肝脏中异常脂质氧化损伤的作用。
7.小鼠血清中炎症因子含量
方法：使用小鼠IL-6 ELISA试剂盒、TNF-α ELISA试剂盒和IL-1βELISA试剂盒分别对处死后小鼠血清中的炎症因子IL-6、TNF-α及IL-1β含量进行测试。
结果：如图6所示，经过4周的降糖肽干预后，实验组小鼠血清中IL-6、TNF-α及IL-1β水平与STZ诱导模型组对比，均有了显著性的降低（P < 0.001），表明该降糖肽抑制了糖尿病小鼠血清中炎症因子的异常产生，具有抗炎抑制氧化损伤的作用。
SEQUENCE LISTING
<110> 南京财经大学
南京慕恩生物科技有限公司
<120> 一种降糖肽及其应用
<130> 20181221
<160> 1
<170> PatentIn version 3.3
<210> 1
<211> 9
<212> PRT
<213> 麦胚清蛋白
<400> 1
Ala Asp Trp Gly Gly Pro Leu Pro His
1 5
Claims (10)
1.一种降糖肽，具有如SEQ ID NO：1所示的氨基酸序列。
2.权利要求1所述降糖肽的修饰肽，其特征在于对降糖肽进行修饰，在降糖肽的N端、C端或中间残基上连接氨基酸、多肽、蛋白质或PEG。
3.根据权利要求2 所述修饰肽，其特征在于对降糖肽的修饰包括：
对降糖肽的N端进行甲酰化或乙酰化，或者在N端连接脂肪酸、肼基烟酰胺、二乙烯三胺五乙酸、肉豆蔻酸、十六酸或琥珀酰胺或PEG ；或者对降糖肽C端进行酰胺化、或在C 端连有p-硝基苯胺或7-氨基-4-甲基香豆素；或者对降糖肽中间残基进行糖基化、磷酸化、甲基化、乙酰化、硝基化、磺酸化或者连接PEG 修饰或者降糖肽中间残基偶联蛋白质。
4.权利要求1 所述降糖肽的修饰肽，其特征在于所述降糖肽的N 端和C 端首尾连接成环。
5.权利要求1 所述降糖肽的修饰肽，其特征在于将所述降糖肽序列中的一种或多种氨基酸替换成相应的氨基酸衍生物或特殊氨基酸。
6.权利要求1 所述降糖肽的修饰肽，其特征在于所述构成多肽序列中的一种或多种氨基酸为D型氨基酸。
7.权利要求1所述降糖肽在制备治疗和/ 或预防糖尿病或高血脂症药物或保健品中的应用。
8.根据权利要求7 所述应用，其特征在于所述药物中含如权利要求1 所述的降糖肽以及药学上可以接受的载体。
9.权利要求2-6之一所述降糖肽的修饰肽在制备治疗和/ 或预防糖尿病或高血脂症药物或保健品中的应用。
10.根据权利要求9所述应用，其特征在于所述药物含如权利要求2-6 之一所述降糖肽的修饰肽以及药学上可以接受的载体。
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| CN115819508A (zh) * | 2022-12-06 | 2023-03-21 | 中国农业大学 | 分离的寡肽及其在制备降血糖药物或食品中的应用 |
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| CN113925953B (zh) * | 2021-10-22 | 2022-06-07 | 完美（广东）日用品有限公司 | 寡肽或其衍生物在制备改善神经管缺陷药物或食品中的应用 |
| CN115819508A (zh) * | 2022-12-06 | 2023-03-21 | 中国农业大学 | 分离的寡肽及其在制备降血糖药物或食品中的应用 |
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