CN113929769B - 一种促进成肌细胞增殖的活性肽及其应用 - Google Patents
一种促进成肌细胞增殖的活性肽及其应用 Download PDFInfo
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- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/78—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
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- 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
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- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
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- A61K38/39—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C07K14/76—Albumins
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- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
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- A—HUMAN NECESSITIES
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Abstract
本发明公开了一种促进成肌细胞增殖的活性肽及其应用。本发明所述活性肽的氨基酸序列如SEQ ID NO:1‑SEQ ID NO:6所示。本发明提供的活性肽可有效促进成肌细胞增殖,有望成为促进骨骼肌增殖再生、对抗肌肉萎缩的先导化合物,且这些多肽具有高效低毒的特点,可以开发成药物。
Description
技术领域
本发明涉及活性肽技术领域。更具体地,涉及一种促进成肌细胞增殖的活性肽及其应用。
背景技术
骨骼肌约占人体体重的40%,是构成人体重要的组织结构,是能量代谢和机体运动的主要器官,在机体受伤和器官受损时拥有较强的自我修复能力。骨骼肌属于终末分化细胞,不能进行补偿性增殖,损伤后只能通过蛋白质合成调控和骨骼肌卫星细胞的增殖与分化进行修复。目前,肌肉萎缩在肿瘤、慢性肾病、慢性阻塞性肺病和心力衰竭等恶病质中及其常见,在长时间不运动、反复运动损伤以及机体衰老过程中,也常常伴随着肌肉萎缩的发生。肌肉组织受损会直接导致运动能力下降,干扰患者日常活动,同时也会导致能量消耗减少,增加患肥胖症和2型糖尿病等代谢性疾病的风险。目前,市场上常见的治疗肌肉萎缩的药物往往具有较强的毒副作用,长时间使用还会产生抗药性。同时,因为机体衰老,许多老年人患有肌少症,导致行动力下降,严重影响老年人的生活质量,而低毒性的延缓肌少症的保健品非常少。近年来,市场上也存在一些酶解骨胶原产品,但是多为混合物,这导致药品开发存在一些隐患。因此,得到纯净的生物活性肽,对于开发抗肌肉萎缩的产品和相关机理研究至关重要。
发明内容
本发明的第一个目的在于提供活性高、毒性小的促进成肌细胞增殖的活性肽。
本发明的第二个目的在于提供上述活性肽在促进成肌细胞增殖、促进骨骼肌增殖再生、对抗肌肉萎缩方面的应用。
为达到上述目的,本发明采用下述技术方案:
根据本发明的第一个目的,本发明提供一种活性肽,所述活性肽的氨基酸序列为如下序列中的一种或多种:
DAGPPGPAGPAGPPGPIG,其中,5位脯氨酸被羟基化修饰形成羟脯氨酸;如SEQ IDNO:1所示;
DAGPPGPAGPAGPPGPIG,其中,4位和14位的脯氨酸被羟基化修饰形成羟脯氨酸;如SEQ ID NO:2所示;
DAGPPGPAGPAGPPGPIG,其中,4位脯氨酸被羟基化修饰形成羟脯氨酸;如SEQ IDNO:3所示;
DAGPPGPAGPAGPPGPIG,其中,5位和14位的脯氨酸被羟基化修饰形成羟脯氨酸;如SEQ ID NO:4所示;
GDAGPPGPAGPAGPPGPIG,其中,5位和15位的脯氨酸被羟基化修饰形成羟脯氨酸;如SEQ ID NO:5所示;
AGPPGPAGPAGPPGPIG,其中,4位和13位的脯氨酸被羟基化修饰形成羟脯氨酸;如SEQ ID NO:6所示。
可选的,所述活性肽还可以是与上述任一活性肽的氨基酸序列具有80%及以上同源性的活性肽,且与上述活性肽的功能相同或相似。例如,所述活性肽的氨基酸序列可以是与上述任一牛骨胶原肽的氨基酸序列具有85%,90%,95%或97%同源性的序列。
本发明还提供了编码上述活性肽的多核苷酸。
在已知活性肽的氨基酸序列的情况下,本领域技术人员可以根据对于活性肽表达的需要,基于密码子的简并性原则和不同物种对于密码子的使用偏好性,设计具有不同核苷酸序列的活性肽的编码基因。
在本发明中,示例性的,上述活性肽的核苷酸序列如序列表SEQ ID NO:9-SEQ IDNO:14所示。
进一步的,本发明提供一种融合多肽,所述融合多肽包含上述的活性肽中的一种。所述的融合多肽可以是通过化学结合、酶切或者物理断裂方法获得。例如将多肽与卵清白蛋白或者牛血清白蛋白形成的蛋白复合体。
本发明的活性肽可以从牛骨胶原蛋白酶解产物中经过分离纯化获得,也可以通过本领域已知的其他方法制备得到,例如固相合成的方法、生物工程的方法等等。
根据本发明的第二个目的,本发明提供所述活性肽在如下任一中的应用:
(1)在制备促进成肌细胞增殖的药物中的应用;
(2)在制备促进骨骼肌增殖再生的药物中的应用;
(3)在制备对抗肌肉萎缩的药物中的应用。
本发明进一步涉及一种药物,其中含有本发明的活性肽,例如DAGPPGPAGPAGPPGPIG(5位脯氨酸被羟基化修饰形成羟脯氨酸),DAGPPGPAGPAGPPGPIG(4位和14位的脯氨酸被羟基化修饰形成羟脯氨酸),DAGPPGPAGPAGPPGPIG(4位脯氨酸被羟基化修饰形成羟脯氨酸),DAGPPGPAGPAGPPGPIG(5位和14位的脯氨酸被羟基化修饰形成羟脯氨酸),GDAGPPGPAGPAGPPGPIG(5位和15位的脯氨酸被羟基化修饰形成羟脯氨酸),AGPPGPAGPAGPPGPIG(4位和13位的脯氨酸被羟基化修饰形成羟脯氨酸)中的一种或多种。
本发明的药物可以制成本领域常见的各种形式,包括但不限于,适于口服的散剂、片剂(包括各种包衣片剂、缓释或控释片剂)、锭剂、胶囊剂(包括软胶囊和硬胶囊)、颗粒剂、丸剂、可分散粉末、水性或油性混悬剂、水性或油性溶液剂、乳剂、酏剂、糖浆剂等等,适于局部使用的霜剂、软膏剂、凝胶、水性或油性溶液剂、水性或油性混悬剂等等;适于吸入使用的粉末或液体气雾剂;适于经胃肠外给药的静脉内、皮下或肌内注射用无菌水性或油性的注射剂或冻干粉针剂、栓剂等等。
本发明的药物中可以进一步含有常规的各种辅料和/或其他活性成分。合适的辅料包括但不限于赋形剂、润滑剂、粘合剂、崩解剂、水溶性聚合物、无机盐、溶剂、溶解助剂、悬浮剂、等渗剂、缓冲液、防腐剂、抗氧剂、着色剂、甜味剂、酸味剂、起泡剂和调味剂等等。
本发明的有益效果如下:
本发明以促进成肌细胞C2C12增殖为活性筛选指标,依次采用反相硅胶柱层析、离子交换柱层析、凝胶柱层析、反向硅胶柱层析,最终筛选到活性最强的组分,并采用高效液相色谱质谱联用仪对活性最强的组分进行氨基酸序列的鉴定。本发明获得活性肽具有一定的促进成肌细胞增殖的作用,有望能够成为促进骨骼肌增殖再生、对抗肌肉萎缩的先导化合物,为肌肉组织受伤后恢复以及治疗相关疾病的药物开发提供一定的指导。
附图说明
下面结合附图对本发明的具体实施方式作进一步详细的说明。
图1示出超滤组分CP-1的快速反相柱层析色谱图。
图2示出超滤组分经过快速反相硅胶柱层析得到的5个组分的成肌细胞增殖检验结果。
图3示出快速反相硅胶柱层析组分CP-1-4的离子交换色谱图
图4示出离子交换柱层析的2个组分的成肌细胞增殖检验结果。
图5示出离子交换柱层析组分CP-1-4-A的凝胶柱层析色谱图
图6示出CP-1-4-A经过凝胶柱层析得到的2个组分的成肌细胞增殖检验结果。
图7示出凝胶色谱柱层析组分CP-1-4-A-A1的快速反相硅胶柱层析色谱图。
图8示出CP-1-4-A-A1经过快速反相硅胶柱层析得到的3个组分的成肌细胞增殖检验结果。
图9示出快速反相硅胶柱层析组分CP-1-4-A-A1-a的高效液相色谱图。
图10示出CP-1-4-A-A1-a经过高效液相色谱仪分离所得的5个组分的成肌细胞增殖检验结果。
图11示出鉴定所得8条肽的成肌细胞增殖检验结果。
具体实施方式
为了更清楚地说明本发明,下面结合优选实施例和附图对本发明做进一步的说明。本领域技术人员应当理解,下面所具体描述的内容是说明性的而非限制性的,不应以此限制本发明的保护范围。
实施例1活性肽制备
为了得到牛骨胶原中能够促进成肌细胞C2C12增殖的多肽,我们对牛骨胶原进行分离纯化。我们主要通过快速蛋白液相色谱(FPLC)(AKTAAVANT 150,GE,Healthcare,Uppsala,瑞典)和HPLC系统(LC-20AR,Shimadzu,京都,日本)来分离纯化牛骨胶原蛋白。所有样品装载到色谱柱上进行分离以及进行细胞实验之前,都需要使用0.22μm的一次性滤膜进行过滤。
依据中国专利申请CN 105586379 A“一种具有抑制癌细胞增殖作用的胶原蛋白活性肽的制备方法”公开的内容,获得超滤组分CP1,即完成该专利申请中所公开的制备方法的步骤(1)-(8)。
1.ODS-AQ反向硅胶柱色谱层析。将超滤组分CP-1(即CP1)装入ODS-AQ柱(50μm;2.5mm×100mm),然后使用超纯水和乙醇为洗脱体系,乙醇梯度洗脱(0%,10分钟;3、6、10和13%,分别为20分钟;17%,5分钟,22%,10分钟,100%,12分钟),流速为5mL/min。检测220nm处洗脱液中的峰值,可以得到5个组分,如图1。将洗脱产物冷冻干燥后,用于促进成肌细胞增殖实验,并使用MTT检测实验结果,如图2所示。根据结果可以发现CP-1-4的促进成肌细胞增殖的作用最强。因此,将CP-1-4进行进一步的分离纯化。
2.离子交换色谱层析。将CP-1-4装入1mL的Hitrap Capto S柱,使用超纯水-NaCl溶液为洗脱液,NaCl溶液浓度从0到1M线性增加,以流速为1mL/min进行洗脱。检测220nm处洗脱成分,可以得到2个组分,结果如图3所示。之后进行细胞增殖实验,MTT检测结果如图4所示。根据结果可以发现CP-1-4-A具有更强的促进成肌细胞增殖的效果。因此,将进一步分离纯化CP-1-4-A。
3.凝胶柱层析。为了进一步纯化,将CP-1-4-A装载到Sephadex G-25柱(90μm,26mm×100mm)上,用超纯水进行洗脱,流量为20mL/min,检测280nm处洗脱组分,结果如图5所示。图6是上述分离所得组分进行促进成肌细胞增殖的结果。可以发现CP-1-4-A-A1促进成肌细胞增殖效果最好。因此,我们将进一步分离CP-1-4-A-A1。
4.ODS-A反向硅胶色谱法。将CP-1-4-A-A1装载在ODS-A柱上(20μm;10mm×100mm),使用超纯水-乙醇进行洗脱,乙醇浓度从0到100%线性梯度洗脱2小时,流速为1mL/min,检测220nm处分离组分,结果如图7所示。将上述所得组分进行细胞增殖检测,结果如图8所示。根据结果可以发现,CP-1-4-A-A1-a具有最强的促进成肌细胞增殖的作用。因此,将CP-1-4-A-A1-a进行进一步分离纯化。
5.高效液相色谱法(HPLC)。
将CP-1-4-A-A1-a装载到连接到HPLC系统的Shim-pack giss C18 HPLC色谱柱中,使用超纯水-乙腈进行洗脱,其中乙腈的线性梯度为0-100%,洗脱2小时,流速为1mL/min。检测220nm处分离组分,可以得到5种组分,结果如图9所示。将上述5种组分进行促进成肌细胞增殖检测,结果如图10所示,可以发现,CP-1-4-A-A1-a-1和CP-1-4-A-A1-a-3具有较强的促进成肌细胞增殖的作用。
通过利用液相色谱质谱联用仪对活性最强的组分CP-1-4-A-A1-a-1和CP-1-4-A-A1-a-3进行氨基酸序列分析,共鉴定得到8条活性肽。结果见表1。
表1从牛骨胶原蛋白酶解液中鉴定到的活性肽序列
P:表示羟基化修饰
实施例2
基于实施例1鉴定得到的8种活性肽的氨基酸序列,通过固相合成方法获得实验样品,进行促进成肌细胞增殖活性验证。固相合成肽公司:吉尔生化(上海)有限公司。如图11所示,8种活性肽中有6种活性肽(DAGPPGPAGPAGPPGPIG(5位脯氨酸被羟基化修饰形成羟脯氨酸),DAGPPGPAGPAGPPGPIG(4位和14位的脯氨酸被羟基化修饰形成羟脯氨酸),DAGPPGPAGPAGPPGPIG(4位脯氨酸被羟基化修饰形成羟脯氨酸),DAGPPGPAGPAGPPGPIG(5位和14位的脯氨酸被羟基化修饰形成羟脯氨酸),GDAGPPGPAGPAGPPGPIG(5位和15位的脯氨酸被羟基化修饰形成羟脯氨酸),AGPPGPAGPAGPPGPIG(4位和13位的脯氨酸被羟基化修饰形成羟脯氨酸))具有一定的促进成肌细胞增殖的作用,说明6种活性肽可以促进成肌细胞增殖、有望能够成为促进骨骼肌增殖再生、对抗肌肉萎缩的先导化合物。其中,3种活性肽(GDAGPPGPAGPAGPPGPIG(5位和15位的脯氨酸被羟基化修饰形成羟脯氨酸),AGPPGPAGPAGPPGPIG(4位和13位的脯氨酸被羟基化修饰形成羟脯氨酸),DAGPPGPAGPAGPPGPIG(5位和14位的脯氨酸被羟基化修饰形成羟脯氨酸))促进成肌细胞增殖作用优于其他几种。
成肌细胞增殖的检测
首先将C2C12成肌细胞以500个/孔的密度接种于96孔板中,在37℃、5%CO2浓度的恒温恒湿的细胞培养箱中培养24h。待细胞贴壁后,吸去培养液,加入不同浓度筛选的活性肽(浓度分别为:0.01mg/mL,0.05mg/mL,0.5mg/mL),并设置空白对照组,每组设置三个复孔。继续培养培养24h后,每孔加入20μL 5mg/mL MTT。继续在培养箱中培养4h后,吸取培养液,每孔加入150μL二甲基亚砜(DMSO)。最后在490nm波长下,在酶标仪上进行吸光度A的测定,并计算其细胞相对存活率。
细胞相对生存率(%)=As/Ac×100
公式中:As:活性肽样品吸光度的平均值;Ac:空白对照吸光度的平均值。
显然,本发明的上述实施例仅仅是为清楚地说明本发明所作的举例,而并非是对本发明的实施方式的限定,对于所属领域的普通技术人员来说,在上述说明的基础上还可以做出其它不同形式的变化或变动,这里无法对所有的实施方式予以穷举,凡是属于本发明的技术方案所引伸出的显而易见的变化或变动仍处于本发明的保护范围之列。
SEQUENCE LISTING
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Claims (3)
1.一种活性肽,其特征在于,所述活性肽的氨基酸序列为:
DAGPPGPAGPAGPPGPIG,其中,5位和14位的脯氨酸被羟基化修饰形成羟脯氨酸;或,
GDAGPPGPAGPAGPPGPIG,其中,5位和15位的脯氨酸被羟基化修饰形成羟脯氨酸。
2.权利要求1所述的活性肽在制备促进成肌细胞增殖的药物中的应用。
3.一种药物,其特征在于,包含权利要求1所述的活性肽。
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Cell Proliferation Stimulation Ability and Osteogenic Activity of Low Molecular Weight Peptides Derived from Bovine Gelatin Hydrolysates;Jianing Wang等;J. Agric. Food Chem;第68卷;第7630−7640页 * |
Urinary peptidomics provides a noninvasive humanized readout of diabetic nephropathy in mice;Julie Klein等;Kidney International;第90卷;补充表2 * |
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