CN108822209A - 多肽、其生产方法和用途 - Google Patents
多肽、其生产方法和用途 Download PDFInfo
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- CN108822209A CN108822209A CN201810736734.4A CN201810736734A CN108822209A CN 108822209 A CN108822209 A CN 108822209A CN 201810736734 A CN201810736734 A CN 201810736734A CN 108822209 A CN108822209 A CN 108822209A
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Abstract
本发明涉及多肽、其生产方法和用途。所述多肽包含N端区域和C端区域。本发明的多肽黏附效果明显优于商品化的人胶原蛋白的黏附效果。
Description
技术领域
本发明属于基因工程技术领域，涉及多肽、其生产方法和用途。
背景技术：
胶原蛋白一般为白色、透明、无分支的原纤维，是皮肤和骨骼的基础支撑物，可以占到蛋白质总量的25％～35％，主要分布于人体的皮肤、血管、骨骼、筋腱、牙齿和软骨等处，是这些组织的主要基质和支架，保护并连结各种组织，在体内发挥着重要的生理功能。因此，胶原蛋白可以广泛的应用在医药和化妆品等行业中。
当前市场上销售的胶原蛋白产品都是取自猪、牛、鱼等动物组织中。以胶原蛋白的氨基酸组成而言：哺乳动物猪、牛与人的相似度为95％，鱼与人的相似度65％。虽然哺乳动物猪、牛等与人的胶原蛋白相似度较高，其仍然难以避免病毒感染以及致敏性的危险。而食用鱼类所萃取的胶原蛋白人体的利用率低于65％，无法完全被人体吸收与利用。所以其常用于食品运用，少部分运用于化妆品，但无法被用于医疗器材或较精密的组织工程产品。所以，目前的胶原蛋白只能在化妆品和保健品中使用，根本无法发挥胶原蛋白的原本生物学功能。
从结构上来说，人体天然的胶原蛋白的结构非常的复杂，所以才导致人源胶原蛋白极难通过常规手段表达和大量制备。胶原蛋白最普遍的结构特征是由3条肽链形成的三螺旋结构，即由3条A肽链以右手超螺旋方式形成蛋白质，这样的三股螺旋区域被称为胶原区域。每个A肽链在分子结构上都是由重复出现的Gly-X-Y(X、Y代表Gly之外的任何氨基酸残基，X往往是Pro，Y往往是Hyp)肽段构成左手螺旋，3条链在氨基酸残基的相互作用下，以同一轴为中心，以右手超螺旋方式形成稳定的三股螺旋结构。在生物体中，胶原蛋白的合成和修饰从原胶原开始，经历了羟基化、糖基化、相互交联等诸多化学变化，受到了多种生物酶的复杂调控。原胶原除了含有胶原链之外，还含有球状的头部和尾部。没有这些头部和尾部，胶原链就不会折叠成为正确的三螺旋，从而缺乏胶原蛋白的生物学活性。因此，按照原始基因序列制备的胶原蛋白不可能在体外自发的组织形成正确的空间结构。这样的困难严重阻碍了人胶原蛋白的研发和生产。
生产胶原蛋白的传统方法是利用酸、碱、酶解法处理动物来源的组织，提取胶原蛋白衍生物。这些方法提取的胶原蛋白本身已经丧失了原本的生物学活性，无法应用于生物医学领域发挥真正的功能。大多数经过制备后的胶原蛋白产品，拉伸强度较弱；纯胶原蛋白在体内降解较快，以及可能存在潜在的抗原性等，同时由于胶原蛋白的来源、加工工艺和原料配比的差异，产品的营养成分及饲用价值也不相同，且皮料在加工过程中不仅要接触许多化学物质，且易受到细菌的感染，严重限制了胶原蛋白的应用。虽然国外研究机构通过培育含人胶原蛋白基因的小鼠，得到了含有人胶原蛋白的乳汁，但是这样生产的成本过高，生产周期过长，无法投入大规模生产。
发明内容
针对上述现有技术的缺陷，本发明提供了：
1.多肽，所述多肽包含N端区域和C端区域，
其中所述N端区域包含SEQ ID No.13中的至少48个连续的氨基酸残基的N端序列；
其中所述C端区域包含以SEQ ID No.14所示的序列GPPGPCCGGG；
其中优选地，所述多肽是胶原蛋白多肽，优选是人源胶原蛋白多肽；
其中优选地，所述N端区域包含N端序列的n个重复，n为大于等于1的整数，优选地为1、2、3、4、5、6、7、8、9或10；
其中优选地，当n为大于等于2的整数时，各个N端序列是连续的或者间隔1个或多个氨基酸残基；
其中优选地，所述N端区域与C端区域是连续的或者间隔1个或多个氨基酸残基。
2.根据项1所述的多肽，其中所述N端序列包含选自SEQ ID No.1、SEQ ID No.2、SEQ ID No.3和SEQ ID No.4的序列。
3.根据项1或2所述的多肽，其包含SEQ ID No.5、SEQ ID No.7、SEQ ID No.9、或SEQ ID No.11的氨基酸序列。
4.多核苷酸，其编码根据权利要求1-3中任一项所述的多肽，其中所述多核苷酸优选是SEQ ID No.6、SEQ ID No.8、SEQ ID No.10、或SEQ ID No.12。
5.表达载体，其包含根据4所述的多核苷酸。
6.宿主细胞，其包含根据5所述的表达载体，其中所述宿主细胞优选是大肠杆菌。
7.根据权利要求1所述的多肽的生产方法，其包括：
(1)在生产培养基中培养根据6所述的宿主细胞并生产多肽；
(2)收获并纯化多肽；和
(3)任选地对多肽进行酶切。
8.组合物，优选医疗器材、组织工程产品、化妆品或保健品，其包含根据1所述的多肽。
9.根据1所述的多肽在制备组合物，优选医疗器材、组织工程产品、化妆品、保健品中的用途。
10.根据1所述的多肽促进细胞粘附的用途。
与现有技术相比，本发明具有以下特点：
(1)本发明首次选择的II型胶原蛋白序列为长期筛选优化的序列；
(2)采用大肠杆菌表达系统，适于大规模放大，20小时即可完成一轮发酵，生产成本非常低，由于对基因序列进行了大肠杆菌的密码子优化以及选用2×YT培养基，使得产量非常大；
(3)生产的重组人源胶原蛋白具有非常好的亲水性和稳定性，其氨基酸组成与天然胶原蛋白氨基酸序列相应部分100％相同，应用于人体不会产生免疫排斥和过敏反应，可以广泛应用于生物医药和化妆品行业；
(4)本发明产品经过活性检测，具有达到甚至超过人体天然蛋白的生物学活性，是目前报道过的最优化的胶原蛋白设计方案，可以在人体中行使天然蛋白的功能，达到真正的产品应用的目的。
附图说明
图1为本发明载体pET32a-C2R1T、pET32a-C2R4T、PET32a-C2R5T、PET32a-C2R10T构建的质粒图谱；
图2为本发明C2R1T蛋白纯化酶切后得到的目的蛋白电泳图；C2R1T蛋白的电泳检测分子量约为30kDa，对应于包含SEQ ID NO.5的氨基酸序列的蛋白质。
图3为本发明C2R4T蛋白纯化酶切后得到的目的蛋白电泳图；C2R4T蛋白的电泳检测分子量约为36kDa，对应于包含SEQ ID NO.7的氨基酸序列的蛋白质。
图4为本发明C2R5T蛋白纯化酶切后得到的目的蛋白电泳图；C2RT1蛋白的电泳检测分子量约为34kDa，对应于包含SEQ ID NO.9的氨基酸序列的蛋白质。
图5为本发明C2R10T蛋白纯化酶切后得到的目的蛋白电泳图；C2RT1蛋白的电泳检测分子量约为25kDa，对应于包含SEQ ID NO.11的氨基酸序列的蛋白质。
图6为本发明C2R1T蛋白与人胶原蛋白相比较的生物活性检测结果。
图7为本发明C2R4T蛋白与人胶原蛋白相比较的生物活性检测结果。
图8为本发明C2R5T蛋白与人胶原蛋白相比较的生物活性检测结果。
图9为本发明C2R10T蛋白与人胶原蛋白相比较的生物活性检测结果。
具体实施方式
下文提供进一步的描述以便于理解本发明。
如本文中使用，“医疗器械”是指直接或者间接用于人体的仪器、设备、器具、体外诊断试剂及校准物、材料以及其他类似或者相关的物品。
如本文中使用，“组织工程产品”是指用于组织工程的产品。组织工程是一门以细胞生物学和材料科学相结合，进行体外或体内构建组织或器官的新兴学科。
在本发明中，选择II型胶原蛋白序列为筛选优化的序列。所述人胶原II型的序列是NCBI参照序列：NM_001844.4(SEQ ID No.13)，参见https://www.ncbi.nlm.nih.gov/nuccore/NM_001844.4。
上述序列中粗体下划线部分即为本发明选择的氨基酸序列。申请人经过大量的研究发现，选择的上述序列比商品化的人胶原蛋白或SEQ ID No.13中的其他序列实现更好的粘附效果。在本发明中，多肽不是SEQ ID No.13的全长序列。
本发明部分基于以下发现：包含SEQ ID No.13中的至少48个连续的氨基酸残基的N端区域和以SEQ ID No.14所示的序列GPPGPCCGGG的C端区域的多肽能够比商品化的人胶原蛋白实现更好的粘附效果，如实施例证明。本领域技术人员可以适当选择构成N端区域的连续的氨基酸残基。例如，连续的氨基酸残基的长度可以是48-100、50-72、54-57、48-72等等。
在本发明中，对几种具体的N端区域的序列进行了测试：
(1)GPSGKDGPKGARGDSGPPGRAGEPGLQGPAGPPGEKGEPGDDGPSGAEGPPGPQ(SEQ IDNo.1)；
(2)GDPGRPGEPGLPGARGLTGRPGDAGPQGKVGPSGAPGEDGRPGPPGPQGARGQPGVMGFPGPKGANGEPGKA(SEQ ID No.2)；
(3)GPPGADGQPGAKGEQGEAGQKGDAGAPGPQGPSGAPGPQGPTGVTGPKGARGAQGPP(SEQ IDNo.3)；
(4)GEAGAQGPMGPSGPAGARGIQGPQGPRGDKGEAGEPGERGLKGHRGFT(SEQ ID No.4)。
在本发明中，C端氨基酸序列可以为GPPGPCCGGG(SEQ ID No.14)，该序列增强胶原活性的端序列肽段。
多肽在本文中可以是重组人源胶原蛋白C2R1T，为单链结构，包括氨基酸226个，基本重复单元为GPSGKDGPKGARGDSGPPGRAGEPGLQGPAGPPGEKGEPGDDGPSGAEGPPGPQ(SEQ IDNo.1)，为人胶原蛋白II型肽段，C端氨基酸序列为GPPGPCCGGG(SEQ ID No.14)，为增强胶原活性的端序列肽段。C2R1T的氨基酸序列如下：GPSGKDGPKGARGDSGPPGRAGEPGLQGPAGPPGEKGEPGDDGPSGAEGPPGPQGPSGKDGPKGARGDSGPPGRAGEPGLQGPAGPPGEKGEPGDDGPSGAEGPPGPQGPSGKDGPKGARGDSGPPGRAGEPGLQGPAGPPGEKGEPGDDGPSGAEGPPGPQGPSGKDGPKGARGDSGPPGRAGEPGLQGPAGPPGEKGEPGDDGPSGAEGPPGPQGPPGPCCGGG(SEQ ID No.5)。C2R1T的DNA序列如下：GGTCCTAGTGGTAAAGATGGTCCGAAAGGTGCACGTGGTGATAGTGGTCCGCCGGGTCGTGCAGGTGAACCGGGTCTGCAGGGTCCGGCAGGTCCGCCTGGTGAGAAAGGTGAACCGGGCGATGATGGGCCGAGCGGTGCCGAAGGTCCTCCTGGTCCGCAAGGTCCGTCTGGTAAAGATGGGCCGAAAGGTGCCAGAGGGGATAGTGGGCCGCCGGGTAGAGCAGGTGAACCTGGGCTGCAGGGTCCTGCAGGTCCGCCAGGTGAAAAAGGGGAACCAGGTGATGATGGACCAAGCGGTGCAGAAGGTCCGCCGGGCCCTCAGGGTCCTAGCGGTAAAGATGGCCCGAAAGGTGCGAGAGGTGATAGCGGACCGCCGGGAAGAGCAGGAGAACCAGGACTGCAGGGACCGGCAGGTCCTCCGGGTGAAAAAGGTGAACCAGGTGACGATGGGCCGAGTGGTGCAGAAGGACCGCCGGGTCCGCAGGGACCAAGCGGCAAAGACGGACCGAAAGGAGCAAGAGGAGATAGTGGACCGCCGGGCCGGGCAGGTGAACCAGGCTTACAGGGTCCGGCGGGTCCGCCAGGAGAAAAAGGGGAGCCGGGTGATGATGGGCCAAGCGGAGCAGAAGGACCTCCGGGTCCGCAAGGACCTCCAGGTCCATGTTGTGGAGGTGGG(SEQ ID No.6)。
多肽在本文中可以是人源胶原蛋白C2R4T，为单链结构，包括298个氨基酸，基本重复单元为GDPGRPGEPGLPGARGLTGRPGDAGPQGKVGPSGAPGEDGRPGPPGPQGARGQPGVMGFPGPKGANGEPGKA(SEQ ID No.2)，为人胶原蛋白II型肽段，C端氨基酸序列为GPPGPCCGGG(SEQ IDNo.14)，为增强胶原活性的端序列肽段。C2R4T的氨基酸序列如下：GDPGRPGEPGLPGARGLTGRPGDAGPQGKVGPSGAPGEDGRPGPPGPQGARGQPGVMGFPGPKGANGEPGKAGDPGRPGEPGLPGARGLTGRPGDAGPQGKVGPSGAPGEDGRPGPPGPQGARGQPGVMGFPGPKGANGEPGKAGDPGRPGEPGLPGARGLTGRPGDAGPQGKVGPSGAPGEDGRPGPPGPQGARGQPGVMGFPGPKGANGEPGKAGDPGRPGEPGLPGARGLTGRPGDAGPQGKVGPSGAPGEDGRPGPPGPQGARGQPGVMGFPGPKGANGEPGKAGPPGPCCGGG(SEQ ID No.7)。C2R4T的DNA序列如下：GGTGATCCGGGTCGTCCGGGTGAACCGGGTCTGCCTGGTGCGCGTGGTCTGACAGGTCGTCCGGGAGATGCGGGGCCGCAGGGTAAAGTTGGGCCGAGCGGGGCGCCGGGTGAAGATGGTCGTCCGGGCCCTCCGGGTCCGCAAGGTGCAAGAGGTCAGCCTGGTGTTATGGGTTTTCCTGGTCCGAAAGGTGCAAATGGGGAGCCGGGTAAAGCAGGTGATCCGGGAAGACCGGGTGAACCTGGTCTGCCTGGCGCCAGAGGGTTAACAGGTCGTCCTGGTGATGCAGGTCCGCAGGGTAAGGTTGGTCCGTCGGGAGCACCGGGTGAAGACGGTAGACCGGGTCCGCCTGGGCCGCAAGGTGCTAGAGGTCAGCCGGGTGTGATGGGTTTTCCGGGTCCGAAAGGGGCAAATGGGGAACCGGGTAAAGCGGGGGACCCTGGGCGTCCAGGTGAACCTGGCCTGCCGGGTGCAAGAGGATTAACAGGTCGGCCGGGGGATGCAGGTCCTCAAGGGAAAGTGGGTCCGAGCGGTGCACCGGGTGAGGATGGGAGACCGGGTCCTCCGGGGCCACAAGGTGCACGTGGTCAGCCGGGGGTGATGGGTTTCCCGGGGCCTAAAGGGGCAAACGGTGAGCCGGGTAAGGCAGGTGATCCAGGTCGGCCGGGTGAACCAGGTCTGCCGGGTGCTCGTGGTTTAACAGGTCGCCCGGGTGATGCGGGTCCTCAGGGTAAAGTGGGTCCTAGCGGGGCACCTGGAGAAGATGGGCGTCCGGGTCCTCCTGGGCCGCAGGGCGCACGTGGTCAACCTGGTGTTATGGGGTTTCCTGGTCCTAAAGGTGCAAACGGGGAACCGGGCAAAGCAGGACCGCCGGGTCCGTGTTGTGGTGGTGGT(SEQ IDNo.8)。
多肽在本文中可以是人源胶原蛋白C2R5T，为单链结构，包括氨基酸238个，基本重复单元为GPPGADGQPGAKGEQGEAGQKGDAGAPGPQGPSGAPGPQGPTGVTGPKGARGAQGPP(SEQ IDNo.3)，为人胶原蛋白II型肽段，C端氨基酸序列为GPPGPCCGGG(SEQ ID No.14)，为增强胶原活性的端序列肽段。C2R5T的氨基酸序列如下：GPPGADGQPGAKGEQGEAGQKGDAGAPGPQGPSGAPGPQGPTGVTGPKGARGAQGPPGPPGADGQPGAKGEQGEAGQKGDAGAPGPQGPSGAPGPQGPTGVTGPKGARGAQGPPGPPGADGQPGAKGEQGEAGQKGDAGAPGPQGPSGAPGPQGPTGVTGPKGARGAQGPPGPPGADGQPGAKGEQGEAGQKGDAGAPGPQGPSGAPGPQGPTGVTGPKGARGAQGPPGPPGPCCGGG(SEQ ID No.9)。C2R5T的DNA序列如下：
GGTCCTCCTGGTGCAGATGGTCAGCCGGGTGCAAAAGGTGAACAGGGTGAAGCAGGTCAGAAAGGTGATGCAGGGGCACCGGGTCCGCAGGGTCCTAGTGGTGCACCGGGTCCTCAGGGTCCGACCGGTGTAACCGGTCCGAAAGGAGCAAGAGGTGCACAGGGACCGCCGGGTCCACCGGGTGCAGATGGACAGCCTGGTGCAAAAGGGGAACAGGGTGAGGCAGGTCAGAAGGGTGATGCAGGTGCACCAGGACCGCAGGGACCGAGCGGTGCACCAGGTCCTCAGGGCCCAACCGGGGTTACCGGTCCGAAGGGGGCAAGAGGAGCACAGGGACCACCGGGACCACCGGGTGCTGATGGTCAGCCTGGAGCAAAAGGAGAACAGGGGGAAGCAGGGCAAAAAGGAGATGCAGGTGCGCCGGGACCGCAGGGTCCAAGTGGAGCACCAGGACCACAAGGACCGACCGGTGTGACGGGTCCGAAAGGGGCAAGAGGGGCACAGGGACCTCCAGGTCCGCCGGGTGCAGACGGTCAGCCTGGTGCTAAAGGGGAACAAGGAGAAGCAGGACAAAAAGGAGACGCAGGTGCGCCAGGACCGCAAGGTCCGAGCGGTGCTCCAGGTCCACAGGGTCCCACCGGTGTTACAGGTCCAAAAGGGGCACGCGGAGCACAGGGGCCGCCAGGTCCTCCTGGACCTTGTTGTGGTGGTGGT(SEQ ID No.10)。
多肽在本文中可以是人源胶原蛋白C2R10T，为单链结构，包括氨基酸202个，基本重复单元为
GEAGAQGPMGPSGPAGARGIQGPQGPRGDKGEAGEPGERGLKGHRGFT(SEQ ID No.4)，为人胶原蛋白II型肽段，C端氨基酸序列为GPPGPCCGGG，为增强胶原活性的端序列肽段。C2R10T的氨基酸序列如下：
GEAGAQGPMGPSGPAGARGIQGPQGPRGDKGEAGEPGERGLKGHRGFTGEAGAQGPMGPSGPAGARGIQGPQGPRGDKGEAGEPGERGLKGHRGFTGEAGAQGPMGPSGPAGARGIQGPQGPRGDKGEAGEPGERGLKGHRGFTGEAGAQGPMGPSGPAGARGIQGPQGPRGDKGEAGEPGERGLKGHRGFTGPPGPCCGGG(SEQ ID No.11)。C2R10T的DNA序列如下：
GGTGAAGCAGGTGCGCAGGGTCCGATGGGGCCGAGTGGTCCTGCGGGTGCAAGAGGAATTCAGGGTCCGCAGGGGCCGAGAGGGGATAAAGGAGAAGCAGGGGAACCGGGTGAAAGAGGGCTGAAAGGTCATAGAGGGTTTACGGGTGAAGCAGGAGCACAGGGACCGATGGGACCGAGCGGACCGGCAGGAGCAAGAGGAATACAGGGACCGCAGGGACCGAGAGGAGATAAAGGTGAAGCAGGGGAGCCGGGAGAAAGAGGACTGAAAGGACATAGAGGATTTACAGGAGAAGCAGGAGCGCAGGGACCGATGGGGCCAAGCGGACCTGCAGGAGCACGGGGAATACAGGGTCCGCAAGGACCGAGAGGGGACAAAGGAGAAGCGGGAGAACCGGGAGAGAGAGGACTGAAGGGACATAGAGGGTTCACGGGTGAAGCCGGAGCACAAGGACCGATGGGTCCGAGCGGGCCGGCAGGTGCAAGAGGTATACAGGGACCACAGGGACCGCGGGGAGATAAAGGAGAGGCAGGAGAACCGGGTGAGAGAGGATTAAAAGGACATCGGGGATTTACCGGTCCGCCGGGACCATGTTGTGGTGGGGGG(SEQ IDNo.12)。
在本发明中，重组人源胶原蛋白可以通过本领域中常规的方法进行。例如，可以如下步骤生产：(1)大肠杆菌基因工程菌的构建；(2)大肠杆菌基因工程菌的发酵培养；(3)重组人源胶原蛋白的诱导和表达；以及(4)重组人源胶原蛋白的纯化和任选的酶切。
在步骤(1)中，大肠杆菌基因工程菌的构建可以如下进行：(1)利用PCR方法对人源性II型胶原蛋白的基因螺旋区的DNA片段进行密码子优化和拼接重组，最终得到目的基因片段；(2)将得到的目的基因片段插入PET-32a表达载体中得到重组表达质粒；(3)将重组表达质粒转入大肠杆菌感受态细胞BL21(DE3)中，筛选得到阳性大肠杆菌基因工程菌。
在步骤(2)与(3)中，大肠杆菌基因工程菌的发酵培养和重组人源胶原蛋白的诱导和表达可以如下进行：(1)从LAB平板中挑取优选后的大肠杆菌基因工程菌单菌落，置于10ml的LB培养基中37℃，220rpm培养12-16小时；(2)将菌液按照1：100接种到2×YT培养基中放大培养，37℃培养约3小时，待OD600在0.4-0.6时，加入终浓度为0.5mM IPTG进行诱导，16℃继续培养20小时，离心收集菌体。
在步骤(4)中，重组人源胶原蛋白多肽的纯化和酶切可以如下进行：(1)用磷酸盐缓冲液(40mM NaH2PO3，500mM NaCl，pH 7.8)重悬细菌，超声破碎，离心收集上清液；(2)利用NI-NTA亲和柱结合重组人源胶原蛋白，10mM咪唑漂洗杂蛋白后，加入PrescissionProtease(PPase)蛋白酶4℃，16h柱上酶切，最后获得目的胶原蛋白多肽。
宿主细胞可以是真核细胞，例如真菌和酵母，原核细胞，例如肠杆菌科细菌。应当理解，本领域技术人员可以通过用其它表达菌株替换上述大肠杆菌菌株作为宿主细胞。
实施例
提供以下实施例来阐述本发明。本领域技术人员应当理解实施例仅仅是例示性的而非限制性的。本发明仅仅由所附权利要求书的范围限定。
实施例1：重组人源胶原蛋白多肽的构建及表达
C2R1T基因表达载体的构建及表达
1.实施例1中使用的人源胶原蛋白C2R1T全长基因序列以SEQ ID No.6显示。该序列已经针对大肠杆菌的密码子进行了密码子优化。
2.C2R1T基因全长678bp，根据优化后的C2R1T密码子基因序列SEQ IDNo.6，委托上海华津生物科技有限公司进行基因片段的合成，并将合成后的C2R1T基因片段通过BamH I(NEB公司货号：R0136L)和Xho I(NEB公司，货号：R0146L)的酶切位点插入PET32a表达载体。将该构建成功的表达质粒转化大肠杆菌感受态细胞BL21(DE3)(Merck公司)。具体过程为：1：取1μl的该质粒于100μl的大肠杆菌感受态细胞BL21(DE3)中，冰上静置30min。2：将该混合物于42℃水浴锅中热激90s，然后迅速置于冰上静置2min。3：向该混合物中加入600μl无抗性的LB，37℃，220rpm条件下培养1h。4：取200μl该菌液均匀的涂布在含有氨苄青霉素抗性的LB平板上(10g/L蛋白胨，5g/L酵母提取物，10g/L氯化钠，15g/L琼脂，100μg/ml氨苄抗生素)。5：将平板倒置培养于37℃温箱中，培养约20h待长出清晰可见的菌落。
3.从转化好的LB平板中挑取单克隆菌落于10ml LB(含100μg/ml氨苄抗生素)培养基中培养12h-16h后，再按照1:100的比例转接到2×YT培养基(16g/L蛋白胨，10g/L酵母提取物，5g/L氯化钠)中进行扩大培养，37℃，220rpm培养至菌液OD600在0.4-0.6时，加入终浓度为0.5mM IPTG(Sigma公司，货号：I5502-1G)进行诱导表达，诱导条件为18℃、180rpm培养20h。最后离心收集菌体，保存于-20℃或者立即进入下步纯化。
4.用磷酸盐缓冲液(pH 7.8)(40mM磷酸二氢钠，500mM氯化钠)约50ml重悬(1L)菌体沉淀，利用高压破菌仪器(新芝生物)进行破菌后，13000rpm离心30min，使可溶性蛋白与包涵体充分分离。
5.用5倍柱体积的结合缓冲液(Binding buffer)(40mM NaH2PO3，500mMNaCl，pH7.8)平衡Ni-NTA(Qiagen公司，货号：30210)亲和柱。然后加入蛋白上清于4℃条件下孵育0.5-1h，使目的重组蛋白充分结合到柱材上。再用200ml含有10mM咪唑(Sigma公司)的洗涤缓冲液(washing buffer)(10mM咪唑，40mM NaH2PO3，500mM NaCl，pH 7.8)漂洗杂蛋白。最后加入适量具有His标签的Prescission Protease(简称PPase)(Sigma,SAE0045)蛋白酶，于4℃孵育16h后，收集穿流液，即为去除载体蛋白的目的胶原蛋白。所得产物透析过夜，冻干为干粉待用。
6.所得C2R1T蛋白利用SDS-PAGE检测纯度。具体过程为：取纯化后的蛋白液40μl，加入10μl 5×的蛋白上样缓冲液(250mM的Tris-HCl(pH:6.8)，10％SDS,0.5％溴酚蓝，50％甘油，5％β-巯基乙醇)，置于100℃沸水中煮10min，然后每孔10μl加入SDS-PAGE蛋白胶中，电压80V跑2h后，用考马斯亮蓝染色液(0.1％考马斯亮蓝R-250，25％异丙醇，10％冰醋酸)进行蛋白染色20min，再利用蛋白脱色液(10％醋酸，5％乙醇)进行脱色。最后与人天然胶原蛋白相对照测量蛋白活性。
C2R4T基因表达载体的构建及表达
1.人源胶原蛋白C2R1T全长基因序列以SEQ ID No.8显示。该序列已经针对大肠杆菌的密码子进行了密码子优化。
2.C2R4T基因全长894bp，根据优化后的C2R4T密码子基因序列，委托上海华津生物科技有限公司进行基因片段的合成，并将合成后的C2R1T基因片段通过BamH I(NEB公司货号：R0136L)和Xho I(NEB公司，货号：R0146L)的酶切位点插入PET32a表达载体。将该构建成功的表达质粒转化大肠杆菌感受态细胞BL21(DE3)(Merck公司)。具体过程为：1：取1μl的该质粒于100μl的大肠杆菌感受态细胞BL21(DE3)中，冰上静置30min。2：将该混合物于42℃水浴锅中热激90s，然后迅速置于冰上静置2min。3：向该混合物中加入600μl无抗性的LB，37℃，220rpm条件下培养1h。4：取200μl该菌液均匀的涂布在含有氨苄青霉素抗性的LAB平板上(10g/L蛋白胨，5g/L酵母提取物，10g/L氯化钠，15g/L琼脂，100μg/ml氨苄抗生素)。5：将平板倒置培养于37℃温箱中，培养约20h待长出清晰可见的菌落。
3.从转化好的LB平板中挑取单克隆菌落于10ml LB(含100μg/ml氨苄抗生素)培养基中培养12h-16h后，再按照1:100的比例转接到2×YT培养基(16g/L蛋白胨，10g/L酵母提取物，5g/L氯化钠)中进行扩大培养，37℃，220rpm培养至菌液OD600在0.4-0.6时，加入终浓度为0.5mM IPTG(Sigma公司，货号：I5502-1G)进行诱导表达，诱导条件为18℃、180rpm培养20h。最后离心收集菌体，保存于-20℃或者立即进入下步纯化。
4.用磷酸盐缓冲液(pH 7.8)(40mM磷酸二氢钠，500mM氯化钠)约50ml重悬(1L)菌体沉淀，利用高压破菌仪器(新芝生物)进行破菌后，13000rpm离心30min，使可溶性蛋白与包涵体充分分离。
5.用5倍柱体积的结合缓冲液(Binding buffer)(40mM NaH2PO3，500mMNaCl，pH7.8)平衡Ni-NTA亲和柱(Qiagen公司,货号：30210)。然后加入蛋白上清于4℃条件下孵育0.5-1h，使目的重组蛋白充分结合到柱材上。再用200ml含有10mM咪唑(Sigma公司)的洗涤缓冲液(washing buffer)(10mM咪唑，40mM NaH2PO3，500mM NaCl，pH 7.8)漂洗杂蛋白。最后加入适量具有His标签的Prescission Protease(简称PPase)蛋白酶(Sigma,SAE0045)，于4℃孵育16h后，收集穿流液，即为去除载体蛋白的目的胶原蛋白。所得产物透析过夜，冻干为干粉待用。
6.所得C2R4T蛋白利用SDS-PAGE检测纯度。具体过程为：取纯化后的蛋白液40μl，加入10μl 5×的蛋白上样缓冲液(250mM的Tris-HCl(pH:6.8)，10％SDS,0.5％溴酚蓝，50％甘油，5％β-巯基乙醇)，置于100℃沸水中煮10min，然后每孔10μl加入SDS-PAGE蛋白胶中，电压80V跑2h后，用考马斯亮蓝染色液(0.1％考马斯亮蓝R-250，25％异丙醇，10％冰醋酸)进行蛋白染色20min，再利用蛋白脱色液(10％醋酸，5％乙醇)进行脱色。最后与人天然胶原蛋白相对照测量蛋白活性。
C2R5T基因表达载体的构建及表达
1.人源胶原蛋白C2R1T全长基因序列以SEQ ID No.10显示。该序列已经针对大肠杆菌的密码子进行了密码子优化。
2.C2R5T基因全长715bp，根据优化后的C2R5T密码子基因序列，委托上海华津生物科技有限公司进行基因片段的合成，并将合成后的C2R1T基因片段通过BamH I(NEB公司货号：R0136L)和Xho I(NEB公司，货号：R0146L)的酶切位点插入PET32a表达载体。将该构建成功的表达质粒转化大肠杆菌感受态细胞BL21(DE3)(Merck公司)。具体过程为：1：取1μl的该质粒于100μl的大肠杆菌感受态细胞BL21(DE3)中，冰上静置30min。2：将该混合物于42℃水浴锅中热激90s，然后迅速置于冰上静置2min。3：向该混合物中加入600μl无抗性的LB，37℃，220rpm条件下培养1h。4：取200μl该菌液均匀的涂布在含有氨苄青霉素抗性的LAB平板上(10g/L蛋白胨，5g/L酵母提取物，10g/L氯化钠，15g/L琼脂，100μg/ml氨苄抗生素)。5：将平板倒置培养于37℃温箱中，培养约20h待长出清晰可见的菌落。
3.从转化好的LB平板中挑取单克隆菌落于10ml LB(含100μg/ml氨苄抗生素)培养基中培养12h-16h后，再按照1:100的比例转接到2×YT培养基(16g/L蛋白胨，10g/L酵母提取物，5g/L氯化钠)中进行扩大培养，37℃，220rpm培养至菌液OD600在0.4-0.6时，加入终浓度为0.5mM IPTG(Sigma公司，货号：I5502-1G)进行诱导表达，诱导条件为18℃、180rpm培养20h。最后离心收集菌体，保存于-20℃或者立即进入下步纯化。
4.用磷酸盐缓冲液(pH 7.8)(40mM磷酸二氢钠，500mM氯化钠)约50ml重悬(1L)菌体沉淀，利用高压破菌仪器(新芝生物)进行破菌后，13000rpm离心30min，使可溶性蛋白与包涵体充分分离。
5.用5倍柱体积的结合缓冲液(Binding buffer)(40mM NaH2PO3，500mM NaCl，pH7.8)平衡Ni-NTA(Qiagen公司,货号：30210)亲和柱。然后加入蛋白上清于4℃条件下孵育0.5-1h，使目的重组蛋白充分结合到柱材上。再用200ml含有10mM咪唑(Sigma公司)的洗涤缓冲液(washing buffer)(10mM咪唑，40mM NaH2PO3，500mM NaCl，pH 7.8)漂洗杂蛋白。最后加入适量具有His标签的Prescission Protease(简称PPase)蛋白酶(Sigma,SAE0045)，于4℃孵育16h后，收集穿流液，即为去除载体蛋白的目的胶原蛋白。所得产物透析过夜，冻干为干粉待用。
6.所得C2R5T蛋白利用SDS-PAGE检测纯度。具体过程为：取纯化后的蛋白液40μl，加入10μl 5×的蛋白上样缓冲液(250mM的Tris-HCl(pH:6.8)，10％SDS,0.5％溴酚蓝，50％甘油，5％β-巯基乙醇)，置于100℃沸水中煮10min，然后每孔10μl加入SDS-PAGE蛋白胶中，电压80V跑2h后，用考马斯亮蓝染色液(0.1％考马斯亮蓝R-250，25％异丙醇，10％冰醋酸)进行蛋白染色20min，再利用蛋白脱色液(10％醋酸，5％乙醇)进行脱色。最后与人天然胶原蛋白相对照测量蛋白活性。
C2R10T基因表达载体的构建及表达
1.人源胶原蛋白C2R1T全长基因序列以SEQ ID No.12显示。该序列已经针对大肠杆菌的密码子进行了密码子优化。
2.C2R10T基因全长606bp，根据优化后的C2R10T密码子基因序列，委托上海华津生物科技有限公司进行基因片段的合成，并将合成后的C2R1T基因片段通过BamH I(NEB公司货号：R0136L)和Xho I(NEB公司，货号：R0146L)的酶切位点插入PET32a表达载体。将该构建成功的表达质粒转化大肠杆菌感受态细胞BL21(DE3)(Merck公司)。具体过程为：1：取1μl的该质粒于100μl的大肠杆菌感受态细胞BL21(DE3)中，冰上静置30min。2：将该混合物于42℃水浴锅中热激90s，然后迅速置于冰上静置2min。3：向该混合物中加入600μl无抗性的LB，37℃，220rpm条件下培养1h。4：取200μl该菌液均匀的涂布在含有氨苄青霉素抗性的LAB平板上(10g/L蛋白胨，5g/L酵母提取物，10g/L氯化钠，15g/L琼脂，100μg/ml氨苄抗生素)。5：将平板倒置培养于37℃温箱中，培养约20h待长出清晰可见的菌落。
3.从转化好的LB平板中挑取单克隆菌落于10ml LB(含100μg/ml氨苄抗生素)培养基中培养12h-16h后，再按照1:100的比例转接到2×YT培养基(16g/L蛋白胨，10g/L酵母提取物，5g/L氯化钠)中进行扩大培养，37℃，220rpm培养至菌液OD600在0.4-0.6时，加入终浓度为0.5mM IPTG(Sigma公司，货号：I5502-1G)进行诱导表达，诱导条件为18℃、180rpm培养20h。最后离心收集菌体，保存于-20℃或者立即进入下步纯化。
4.用磷酸盐缓冲液(pH 7.8)(40mM磷酸二氢钠，500mM氯化钠)约50ml重悬(1L)菌体沉淀，利用高压破菌仪器(新芝生物)进行破菌后，13000rpm离心30min，使可溶性蛋白与包涵体充分分离。
5.用5倍柱体积的结合缓冲液(Binding buffer)(40mM NaH2PO3，500mM NaCl，pH7.8)平衡Ni-NTA亲和柱(Qiagen公司,货号：30210)。然后加入蛋白上清于4℃条件下孵育0.5-1h，使目的重组蛋白充分结合到柱材上。再用200ml含有10mM咪唑(Sigma公司)的洗涤缓冲液(washing buffer)(10mM咪唑，40mM NaH2PO3，500mM NaCl，pH 7.8)漂洗杂蛋白。最后加入适量具有His标签的Prescission Protease(简称PPase)蛋白酶(Sigma,SAE0045)，于4℃孵育16h后，收集穿流液，即为去除载体蛋白的目的胶原蛋白。所得产物透析过夜，冻干为干粉待用。
6.所得C2R10T蛋白利用SDS-PAGE检测纯度。具体过程为：取纯化后的蛋白液40μl，加入10μl 5x的蛋白上样缓冲液(250mM的Tris-HCl(pH:6.8)，10％SDS,0.5％溴酚蓝，50％甘油，5％β-巯基乙醇)，置于100℃沸水中煮10min，然后每孔10μl加入SDS-PAGE蛋白胶中，电压80V跑2h后，用考马斯亮蓝染色液(0.1％考马斯亮蓝R-250，25％异丙醇，10％冰醋酸)进行蛋白染色20min，再利用蛋白脱色液(10％醋酸，5％乙醇)进行脱色。最后与人天然胶原蛋白相对照测量蛋白活性。
结果
图2-图5的电泳图分别表明得到表观分子量30kDa、36kDa、34kDa和25kDa的C2R1T、C2R4T、C2R5T、和C2R10T，分子量分别对应于SEQ ID NO:5、7、9和11的氨基酸序列的多肽。
实施例2 C2R1T、C2R4T、C2R5T和C2R10T蛋白的活性检测
胶原蛋白的活性检测方法可以参考文献Juming Yao,Satoshi Yanagisawa,Tetsuo Asakura,Design,Expression and Characterization of Collagen-LikeProteins Based on the Cell Adhesive and Crosslinking Sequences Derived fromNative Collagens,J Biochem.136,643-649(2004)。具体实施方法如下：
1、利用紫外吸收法检测待测蛋白样品的浓度，包括对照人胶原蛋白(Sigma，C7774)、C2R1T、C2R4T、C2R5T，和C2R10蛋白样品。具体为分别测定样品在215nm和225nm下的紫外光吸收，利用经验公式C(μg/mL)＝144X(A215-A225)计算蛋白质浓度，注意需在A215<1.5的情况下检测。该方法的原理是测定肽键在远紫外光下的特征吸收，不受生色团含量的影响，干扰物质少，操作简便，适合检测考马斯亮蓝不显色的人胶原蛋白及其类似物。(参考文献为Walker JM.The Protein Protocols Handbook,second edition.HumanaPress.43-45.)。检测完蛋白浓度后，用PBS将所有待测蛋白浓度调整到0.5mg/ml。
2、向96孔板中加入100μl各种蛋白溶液和空白PBS溶液对照，室温静置60min。
3、每孔中加入105个培养状态良好的3T3细胞(来自清华大学童佩老师)，37℃孵育60min。
4、每孔用PBS清洗4次。
5、用LDH检测试剂盒(Roche，04744926001)检测OD492nm的吸光度。根据空白对照的数值，可以计算出细胞的贴壁率。计算公式如下：细胞贴壁率＝(测试孔-空白孔)×100％/(阳性孔-空白孔)。细胞的贴壁率即可以反应胶原蛋白的活性。蛋白的活性越高，越能在短时间给细胞提供优质的外环境，帮助细胞贴壁。
结果参见图6至图9。
图6至图9的结果表明，四种人重组胶原蛋白(即C2R1T、C2R4T、C2R5T，和C2R10)与商品化的人胶原蛋白相比，皆具有很好的黏附活性。其中C2R4T与C2R10T的黏附效果明显优于商品化的人胶原蛋白。
序列表
<110> 山西锦波生物医药股份有限公司
复旦大学
<120> 多肽、其生产方法和用途
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ggtcctagtg gtaaagatgg tccgaaaggt gcacgtggtg atagtggtcc gccgggtcgt 60
gcaggtgaac cgggtctgca gggtccggca ggtccgcctg gtgagaaagg tgaaccgggc 120
gatgatgggc cgagcggtgc cgaaggtcct cctggtccgc aaggtccgtc tggtaaagat 180
gggccgaaag gtgccagagg ggatagtggg ccgccgggta gagcaggtga acctgggctg 240
cagggtcctg caggtccgcc aggtgaaaaa ggggaaccag gtgatgatgg accaagcggt 300
gcagaaggtc cgccgggccc tcagggtcct agcggtaaag atggcccgaa aggtgcgaga 360
ggtgatagcg gaccgccggg aagagcagga gaaccaggac tgcagggacc ggcaggtcct 420
ccgggtgaaa aaggtgaacc aggtgacgat gggccgagtg gtgcagaagg accgccgggt 480
ccgcagggac caagcggcaa agacggaccg aaaggagcaa gaggagatag tggaccgccg 540
ggccgggcag gtgaaccagg cttacagggt ccggcgggtc cgccaggaga aaaaggggag 600
ccgggtgatg atgggccaag cggagcagaa ggacctccgg gtccgcaagg acctccaggt 660
ccatgttgtg gaggtggg 678
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ggtgatccgg gtcgtccggg tgaaccgggt ctgcctggtg cgcgtggtct gacaggtcgt 60
ccgggagatg cggggccgca gggtaaagtt gggccgagcg gggcgccggg tgaagatggt 120
cgtccgggcc ctccgggtcc gcaaggtgca agaggtcagc ctggtgttat gggttttcct 180
ggtccgaaag gtgcaaatgg ggagccgggt aaagcaggtg atccgggaag accgggtgaa 240
cctggtctgc ctggcgccag agggttaaca ggtcgtcctg gtgatgcagg tccgcagggt 300
aaggttggtc cgtcgggagc accgggtgaa gacggtagac cgggtccgcc tgggccgcaa 360
ggtgctagag gtcagccggg tgtgatgggt tttccgggtc cgaaaggggc aaatggggaa 420
ccgggtaaag cgggggaccc tgggcgtcca ggtgaacctg gcctgccggg tgcaagagga 480
ttaacaggtc ggccggggga tgcaggtcct caagggaaag tgggtccgag cggtgcaccg 540
ggtgaggatg ggagaccggg tcctccgggg ccacaaggtg cacgtggtca gccgggggtg 600
atgggtttcc cggggcctaa aggggcaaac ggtgagccgg gtaaggcagg tgatccaggt 660
cggccgggtg aaccaggtct gccgggtgct cgtggtttaa caggtcgccc gggtgatgcg 720
ggtcctcagg gtaaagtggg tcctagcggg gcacctggag aagatgggcg tccgggtcct 780
cctgggccgc agggcgcacg tggtcaacct ggtgttatgg ggtttcctgg tcctaaaggt 840
gcaaacgggg aaccgggcaa agcaggaccg ccgggtccgt gttgtggtgg tggt 894
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ggtcctcctg gtgcagatgg tcagccgggt gcaaaaggtg aacagggtga agcaggtcag 60
aaaggtgatg caggggcacc gggtccgcag ggtcctagtg gtgcaccggg tcctcagggt 120
ccgaccggtg taaccggtcc gaaaggagca agaggtgcac agggaccgcc gggtccaccg 180
ggtgcagatg gacagcctgg tgcaaaaggg gaacagggtg aggcaggtca gaagggtgat 240
gcaggtgcac caggaccgca gggaccgagc ggtgcaccag gtcctcaggg cccaaccggg 300
gttaccggtc cgaagggggc aagaggagca cagggaccac cgggaccacc gggtgctgat 360
ggtcagcctg gagcaaaagg agaacagggg gaagcagggc aaaaaggaga tgcaggtgcg 420
ccgggaccgc agggtccaag tggagcacca ggaccacaag gaccgaccgg tgtgacgggt 480
ccgaaagggg caagaggggc acagggacct ccaggtccgc cgggtgcaga cggtcagcct 540
ggtgctaaag gggaacaagg agaagcagga caaaaaggag acgcaggtgc gccaggaccg 600
caaggtccga gcggtgctcc aggtccacag ggtcccaccg gtgttacagg tccaaaaggg 660
gcacgcggag cacaggggcc gccaggtcct cctggacctt gttgtggtgg tggt 714
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195 200
<210> 12
<211> 606
<212> DNA
<213> 人工序列
<220>
<223> 人源胶原蛋白C2R10T
<400> 12
ggtgaagcag gtgcgcaggg tccgatgggg ccgagtggtc ctgcgggtgc aagaggaatt 60
cagggtccgc aggggccgag aggggataaa ggagaagcag gggaaccggg tgaaagaggg 120
ctgaaaggtc atagagggtt tacgggtgaa gcaggagcac agggaccgat gggaccgagc 180
ggaccggcag gagcaagagg aatacaggga ccgcagggac cgagaggaga taaaggtgaa 240
gcaggggagc cgggagaaag aggactgaaa ggacatagag gatttacagg agaagcagga 300
gcgcagggac cgatggggcc aagcggacct gcaggagcac ggggaataca gggtccgcaa 360
ggaccgagag gggacaaagg agaagcggga gaaccgggag agagaggact gaagggacat 420
agagggttca cgggtgaagc cggagcacaa ggaccgatgg gtccgagcgg gccggcaggt 480
gcaagaggta tacagggacc acagggaccg cggggagata aaggagaggc aggagaaccg 540
ggtgagagag gattaaaagg acatcgggga tttaccggtc cgccgggacc atgttgtggt 600
gggggg 606
<210> 13
<211> 1487
<212> PRT
<213> 人
<400> 13
Met Ile Arg Leu Gly Ala Pro Gln Thr Leu Val Leu Leu Thr Leu Leu
1 5 10 15
Val Ala Ala Val Leu Arg Cys Gln Gly Gln Asp Val Gln Glu Ala Gly
20 25 30
Ser Cys Val Gln Asp Gly Gln Arg Tyr Asn Asp Lys Asp Val Trp Lys
35 40 45
Pro Glu Pro Cys Arg Ile Cys Val Cys Asp Thr Gly Thr Val Leu Cys
50 55 60
Asp Asp Ile Ile Cys Glu Asp Val Lys Asp Cys Leu Ser Pro Glu Ile
65 70 75 80
Pro Phe Gly Glu Cys Cys Pro Ile Cys Pro Thr Asp Leu Ala Thr Ala
85 90 95
Ser Gly Gln Pro Gly Pro Lys Gly Gln Lys Gly Glu Pro Gly Asp Ile
100 105 110
Lys Asp Ile Val Gly Pro Lys Gly Pro Pro Gly Pro Gln Gly Pro Ala
115 120 125
Gly Glu Gln Gly Pro Arg Gly Asp Arg Gly Asp Lys Gly Glu Lys Gly
130 135 140
Ala Pro Gly Pro Arg Gly Arg Asp Gly Glu Pro Gly Thr Pro Gly Asn
145 150 155 160
Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Leu Gly
165 170 175
Gly Asn Phe Ala Ala Gln Met Ala Gly Gly Phe Asp Glu Lys Ala Gly
180 185 190
Gly Ala Gln Leu Gly Val Met Gln Gly Pro Met Gly Pro Met Gly Pro
195 200 205
Arg Gly Pro Pro Gly Pro Ala Gly Ala Pro Gly Pro Gln Gly Phe Gln
210 215 220
Gly Asn Pro Gly Glu Pro Gly Glu Pro Gly Val Ser Gly Pro Met Gly
225 230 235 240
Pro Arg Gly Pro Pro Gly Pro Pro Gly Lys Pro Gly Asp Asp Gly Glu
245 250 255
Ala Gly Lys Pro Gly Lys Ala Gly Glu Arg Gly Pro Pro Gly Pro Gln
260 265 270
Gly Ala Arg Gly Phe Pro Gly Thr Pro Gly Leu Pro Gly Val Lys Gly
275 280 285
His Arg Gly Tyr Pro Gly Leu Asp Gly Ala Lys Gly Glu Ala Gly Ala
290 295 300
Pro Gly Val Lys Gly Glu Ser Gly Ser Pro Gly Glu Asn Gly Ser Pro
305 310 315 320
Gly Pro Met Gly Pro Arg Gly Leu Pro Gly Glu Arg Gly Arg Thr Gly
325 330 335
Pro Ala Gly Ala Ala Gly Ala Arg Gly Asn Asp Gly Gln Pro Gly Pro
340 345 350
Ala Gly Pro Pro Gly Pro Val Gly Pro Ala Gly Gly Pro Gly Phe Pro
355 360 365
Gly Ala Pro Gly Ala Lys Gly Glu Ala Gly Pro Thr Gly Ala Arg Gly
370 375 380
Pro Glu Gly Ala Gln Gly Pro Arg Gly Glu Pro Gly Thr Pro Gly Ser
385 390 395 400
Pro Gly Pro Ala Gly Ala Ser Gly Asn Pro Gly Thr Asp Gly Ile Pro
405 410 415
Gly Ala Lys Gly Ser Ala Gly Ala Pro Gly Ile Ala Gly Ala Pro Gly
420 425 430
Phe Pro Gly Pro Arg Gly Pro Pro Gly Pro Gln Gly Ala Thr Gly Pro
435 440 445
Leu Gly Pro Lys Gly Gln Thr Gly Glu Pro Gly Ile Ala Gly Phe Lys
450 455 460
Gly Glu Gln Gly Pro Lys Gly Glu Pro Gly Pro Ala Gly Pro Gln Gly
465 470 475 480
Ala Pro Gly Pro Ala Gly Glu Glu Gly Lys Arg Gly Ala Arg Gly Glu
485 490 495
Pro Gly Gly Val Gly Pro Ile Gly Pro Pro Gly Glu Arg Gly Ala Pro
500 505 510
Gly Asn Arg Gly Phe Pro Gly Gln Asp Gly Leu Ala Gly Pro Lys Gly
515 520 525
Ala Pro Gly Glu Arg Gly Pro Ser Gly Leu Ala Gly Pro Lys Gly Ala
530 535 540
Asn Gly Asp Pro Gly Arg Pro Gly Glu Pro Gly Leu Pro Gly Ala Arg
545 550 555 560
Gly Leu Thr Gly Arg Pro Gly Asp Ala Gly Pro Gln Gly Lys Val Gly
565 570 575
Pro Ser Gly Ala Pro Gly Glu Asp Gly Arg Pro Gly Pro Pro Gly Pro
580 585 590
Gln Gly Ala Arg Gly Gln Pro Gly Val Met Gly Phe Pro Gly Pro Lys
595 600 605
Gly Ala Asn Gly Glu Pro Gly Lys Ala Gly Glu Lys Gly Leu Pro Gly
610 615 620
Ala Pro Gly Leu Arg Gly Leu Pro Gly Lys Asp Gly Glu Thr Gly Ala
625 630 635 640
Ala Gly Pro Pro Gly Pro Ala Gly Pro Ala Gly Glu Arg Gly Glu Gln
645 650 655
Gly Ala Pro Gly Pro Ser Gly Phe Gln Gly Leu Pro Gly Pro Pro Gly
660 665 670
Pro Pro Gly Glu Gly Gly Lys Pro Gly Asp Gln Gly Val Pro Gly Glu
675 680 685
Ala Gly Ala Pro Gly Leu Val Gly Pro Arg Gly Glu Arg Gly Phe Pro
690 695 700
Gly Glu Arg Gly Ser Pro Gly Ala Gln Gly Leu Gln Gly Pro Arg Gly
705 710 715 720
Leu Pro Gly Thr Pro Gly Thr Asp Gly Pro Lys Gly Ala Ser Gly Pro
725 730 735
Ala Gly Pro Pro Gly Ala Gln Gly Pro Pro Gly Leu Gln Gly Met Pro
740 745 750
Gly Glu Arg Gly Ala Ala Gly Ile Ala Gly Pro Lys Gly Asp Arg Gly
755 760 765
Asp Val Gly Glu Lys Gly Pro Glu Gly Ala Pro Gly Lys Asp Gly Gly
770 775 780
Arg Gly Leu Thr Gly Pro Ile Gly Pro Pro Gly Pro Ala Gly Ala Asn
785 790 795 800
Gly Glu Lys Gly Glu Val Gly Pro Pro Gly Pro Ala Gly Ser Ala Gly
805 810 815
Ala Arg Gly Ala Pro Gly Glu Arg Gly Glu Thr Gly Pro Pro Gly Pro
820 825 830
Ala Gly Phe Ala Gly Pro Pro Gly Ala Asp Gly Gln Pro Gly Ala Lys
835 840 845
Gly Glu Gln Gly Glu Ala Gly Gln Lys Gly Asp Ala Gly Ala Pro Gly
850 855 860
Pro Gln Gly Pro Ser Gly Ala Pro Gly Pro Gln Gly Pro Thr Gly Val
865 870 875 880
Thr Gly Pro Lys Gly Ala Arg Gly Ala Gln Gly Pro Pro Gly Ala Thr
885 890 895
Gly Phe Pro Gly Ala Ala Gly Arg Val Gly Pro Pro Gly Ser Asn Gly
900 905 910
Asn Pro Gly Pro Pro Gly Pro Pro Gly Pro Ser Gly Lys Asp Gly Pro
915 920 925
Lys Gly Ala Arg Gly Asp Ser Gly Pro Pro Gly Arg Ala Gly Glu Pro
930 935 940
Gly Leu Gln Gly Pro Ala Gly Pro Pro Gly Glu Lys Gly Glu Pro Gly
945 950 955 960
Asp Asp Gly Pro Ser Gly Ala Glu Gly Pro Pro Gly Pro Gln Gly Leu
965 970 975
Ala Gly Gln Arg Gly Ile Val Gly Leu Pro Gly Gln Arg Gly Glu Arg
980 985 990
Gly Phe Pro Gly Leu Pro Gly Pro Ser Gly Glu Pro Gly Lys Gln Gly
995 1000 1005
Ala Pro Gly Ala Ser Gly Asp Arg Gly Pro Pro Gly Pro Val Gly
1010 1015 1020
Pro Pro Gly Leu Thr Gly Pro Ala Gly Glu Pro Gly Arg Glu Gly
1025 1030 1035
Ser Pro Gly Ala Asp Gly Pro Pro Gly Arg Asp Gly Ala Ala Gly
1040 1045 1050
Val Lys Gly Asp Arg Gly Glu Thr Gly Ala Val Gly Ala Pro Gly
1055 1060 1065
Ala Pro Gly Pro Pro Gly Ser Pro Gly Pro Ala Gly Pro Thr Gly
1070 1075 1080
Lys Gln Gly Asp Arg Gly Glu Ala Gly Ala Gln Gly Pro Met Gly
1085 1090 1095
Pro Ser Gly Pro Ala Gly Ala Arg Gly Ile Gln Gly Pro Gln Gly
1100 1105 1110
Pro Arg Gly Asp Lys Gly Glu Ala Gly Glu Pro Gly Glu Arg Gly
1115 1120 1125
Leu Lys Gly His Arg Gly Phe Thr Gly Leu Gln Gly Leu Pro Gly
1130 1135 1140
Pro Pro Gly Pro Ser Gly Asp Gln Gly Ala Ser Gly Pro Ala Gly
1145 1150 1155
Pro Ser Gly Pro Arg Gly Pro Pro Gly Pro Val Gly Pro Ser Gly
1160 1165 1170
Lys Asp Gly Ala Asn Gly Ile Pro Gly Pro Ile Gly Pro Pro Gly
1175 1180 1185
Pro Arg Gly Arg Ser Gly Glu Thr Gly Pro Ala Gly Pro Pro Gly
1190 1195 1200
Asn Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Gly Ile
1205 1210 1215
Asp Met Ser Ala Phe Ala Gly Leu Gly Pro Arg Glu Lys Gly Pro
1220 1225 1230
Asp Pro Leu Gln Tyr Met Arg Ala Asp Gln Ala Ala Gly Gly Leu
1235 1240 1245
Arg Gln His Asp Ala Glu Val Asp Ala Thr Leu Lys Ser Leu Asn
1250 1255 1260
Asn Gln Ile Glu Ser Ile Arg Ser Pro Glu Gly Ser Arg Lys Asn
1265 1270 1275
Pro Ala Arg Thr Cys Arg Asp Leu Lys Leu Cys His Pro Glu Trp
1280 1285 1290
Lys Ser Gly Asp Tyr Trp Ile Asp Pro Asn Gln Gly Cys Thr Leu
1295 1300 1305
Asp Ala Met Lys Val Phe Cys Asn Met Glu Thr Gly Glu Thr Cys
1310 1315 1320
Val Tyr Pro Asn Pro Ala Asn Val Pro Lys Lys Asn Trp Trp Ser
1325 1330 1335
Ser Lys Ser Lys Glu Lys Lys His Ile Trp Phe Gly Glu Thr Ile
1340 1345 1350
Asn Gly Gly Phe His Phe Ser Tyr Gly Asp Asp Asn Leu Ala Pro
1355 1360 1365
Asn Thr Ala Asn Val Gln Met Thr Phe Leu Arg Leu Leu Ser Thr
1370 1375 1380
Glu Gly Ser Gln Asn Ile Thr Tyr His Cys Lys Asn Ser Ile Ala
1385 1390 1395
Tyr Leu Asp Glu Ala Ala Gly Asn Leu Lys Lys Ala Leu Leu Ile
1400 1405 1410
Gln Gly Ser Asn Asp Val Glu Ile Arg Ala Glu Gly Asn Ser Arg
1415 1420 1425
Phe Thr Tyr Thr Ala Leu Lys Asp Gly Cys Thr Lys His Thr Gly
1430 1435 1440
Lys Trp Gly Lys Thr Val Ile Glu Tyr Arg Ser Gln Lys Thr Ser
1445 1450 1455
Arg Leu Pro Ile Ile Asp Ile Ala Pro Met Asp Ile Gly Gly Pro
1460 1465 1470
Glu Gln Glu Phe Gly Val Asp Ile Gly Pro Val Cys Phe Leu
1475 1480 1485
<210> 14
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 肽段
<400> 14
Gly Pro Pro Gly Pro Cys Cys Gly Gly Gly
1 5 10
Claims (10)
1.多肽，所述多肽包含N端区域和C端区域，
其中所述N端区域包含SEQ ID No.13中的至少48个连续的氨基酸残基的N端序列；
其中所述C端区域包含以SEQ ID No.14所示的序列GPPGPCCGGG；
其中优选地，所述多肽是胶原蛋白多肽，优选是人源胶原蛋白多肽；
其中优选地，所述N端区域包含N端序列的n个重复，n为大于等于1的整数，优选地为1、2、3、4、5、6、7、8、9或10；
其中优选地，当n为大于等于2的整数时，各个N端序列是连续的或者间隔1个或多个氨基酸残基；
其中优选地，所述N端区域与C端区域是连续的或者间隔1个或多个氨基酸残基。
2.根据权利要求1所述的多肽，其中所述N端序列包含选自SEQ ID No.1、SEQ ID No.2、SEQ ID No.3和SEQ ID No.4的序列。
3.根据权利要求1或2所述的多肽，其包含SEQ ID No.5、SEQ ID No.7、SEQ ID No.9、或SEQ ID No.11的氨基酸序列。
4.多核苷酸，其编码根据权利要求1-3中任一项所述的多肽，其中所述多核苷酸优选是SEQ ID No.6、SEQ ID No.8、SEQ ID No.10、或SEQ ID No.12。
5.表达载体，其包含根据权利要求4所述的多核苷酸。
6.宿主细胞，其包含根据权利要求5所述的表达载体，其中所述宿主细胞优选是大肠杆菌。
7.根据权利要求1所述的多肽的生产方法，其包括：
(1)在生产培养基中培养根据权利要求6所述的宿主细胞并生产多肽；
(2)收获并纯化多肽；和
(3)任选地对多肽进行酶切。
8.组合物，其包含根据权利要求1所述的多肽，其中所述组合物优选是医疗器材、组织工程产品、化妆品或保健品。
9.根据权利要求1所述的多肽在制备组合物，优选医疗器材、组织工程产品、化妆品、保健品中的用途。
10.根据权利要求1所述的多肽促进细胞粘附的用途。
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| CN109593126A (zh) * | 2018-11-28 | 2019-04-09 | 山西锦波生物医药股份有限公司 | 多肽、其生产方法和用途 |
| CN110845603A (zh) * | 2019-10-31 | 2020-02-28 | 中国科学院生物物理研究所 | 人胶原蛋白17型多肽、其生产方法和用途 |
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| CN111944057B (zh) * | 2020-07-23 | 2021-09-10 | 广州启妆生物科技有限公司 | 一种重组人胶原蛋白肽及其应用 |
| CN112898401A (zh) * | 2021-02-05 | 2021-06-04 | 合肥瑞城生生物科技有限公司 | 一种钙网蛋白组合肽及其用途 |
| CN113577248B (zh) * | 2021-07-29 | 2024-02-02 | 山西锦波生物医药股份有限公司 | 重组iii型人源化胶原蛋白的用途 |
| CN113621052B (zh) * | 2021-08-23 | 2022-06-07 | 山西锦波生物医药股份有限公司 | 一种重组i型人源化胶原蛋白多肽及其制备方法和用途 |
| CN113730557B (zh) * | 2021-09-03 | 2023-12-22 | 山西锦波生物医药股份有限公司 | 重组i型人源化胶原蛋白在盆底修复中的用途 |
| CN113683680B (zh) * | 2021-09-15 | 2023-11-03 | 山西锦波生物医药股份有限公司 | 一种重组ⅰ型人源化胶原蛋白c1l1t及其制备方法和用途 |
| CN113683679B (zh) * | 2021-09-15 | 2023-10-31 | 山西锦波生物医药股份有限公司 | 一种重组i型人源化胶原蛋白c1l6t及其制备方法和用途 |
| CN116970071B (zh) * | 2023-09-22 | 2023-12-01 | 英特菲尔(成都)生物制品有限责任公司 | 一种具有抗衰活性的重组弹性蛋白及其制备方法与应用 |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109593126A (zh) * | 2018-11-28 | 2019-04-09 | 山西锦波生物医药股份有限公司 | 多肽、其生产方法和用途 |
| CN109593126B (zh) * | 2018-11-28 | 2019-11-22 | 山西锦波生物医药股份有限公司 | 多肽、其生产方法和用途 |
| US11396537B2 (en) | 2018-11-28 | 2022-07-26 | Shanxi Jinbo Bio-Pharmaceutical Co., Ltd. | Polypeptide, process for the production thereof and use thereof |
| CN110845603A (zh) * | 2019-10-31 | 2020-02-28 | 中国科学院生物物理研究所 | 人胶原蛋白17型多肽、其生产方法和用途 |
| CN110845603B (zh) * | 2019-10-31 | 2021-07-02 | 山西锦波生物医药股份有限公司 | 人胶原蛋白17型多肽、其生产方法和用途 |
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| CN109575126A (zh) | 2019-04-05 |
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