CN109293783B - 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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- CN109293783B CN109293783B CN201811254050.7A CN201811254050A CN109293783B CN 109293783 B CN109293783 B CN 109293783B CN 201811254050 A CN201811254050 A CN 201811254050A CN 109293783 B CN109293783 B CN 109293783B
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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。本发明的多肽具有显著的细胞黏附效果。
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SEQ ID No.1(人I型胶原蛋白COL1A1的全长序 列)中的至少60个连续的氨基酸残基的N端区域和包含以SEQ ID No.2所示 的序列GAPGPCCGG的C端区域，
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端区域为重复n次的基本重复单元，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，优选地n为4；
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1所述的多肽，其中所述N端区域包含选自SEQ ID No.3和SEQ ID No.4的序列。
3.1或2所述的多肽，其包含
a)SEQ ID No.5或SEQ ID No.6的氨基酸序列
b)与SEQ ID No.5或SEQ ID No.6的氨基酸序列具有90％、92％、95％、 96％、97％、98％或99％同一性的氨基酸序列，其保留SEQ ID No.5或SEQ ID No.6的氨基酸序列的细胞黏附效果；
c)SEQ ID No.5或SEQ ID No.6的氨基酸序列中添加、取代、缺失或插 入1个或多个氨基酸残基的氨基酸序列，优选为保守氨基酸取代，所述氨基 酸序列保留SEQ ID No.5或SEQ ID No.6的氨基酸序列的细胞黏附效果；或
d)由核苷酸序列编码的氨基酸序列，所述核苷酸序列与编码SEQ ID No. 5或SEQID No.6的氨基酸序列的多核苷酸序列在严格条件下杂交，其保留 SEQ ID No.5或SEQ IDNo.6的氨基酸序列的细胞黏附效果，所述严格条件 是中等严格条件，中-高严格条件，高严格条件或非常高严格条件。
4.多核苷酸，其编码根据1-3中任一项所述的多肽。
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黏附的用途。
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I型胶原蛋白序列为长期筛选优化的序列；相比于 I型胶原蛋白的其它片段具有显著更好的细胞黏附效果。本发明的重组I型胶 原蛋白片段以较短的序列长度便更好地实现了I型胶原蛋白片段的细胞黏附 活性。
(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为用于本发明载体pET32a-C1S4T(SEQ ID NO.5)、pET32a-C1S5T (SEQ IDNO.6)构建的质粒pET32a的图谱；
图2为本发明C1S4T蛋白纯化酶切后得到的目的蛋白电泳图；C1S4T蛋白 的电泳检测分子量约为36kDa，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C1S5T蛋白纯化酶切后得到的目的蛋白电泳图；C1S5T蛋白 的电泳检测分子量约为36kDa，对应于包含SEQ ID NO.6的氨基酸序列的蛋 白质。
图4为本发明C1S4T蛋白与人胶原蛋白相比较的生物活性检测结果。
图5为本发明C1S5T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I型胶原蛋白序列为筛选优化的序列。所述人胶原I型 COL1A1的序列是NCBI参照序列：NP_000079(SEQ ID No.1)，参见 https://www.ncbi.nlm.nih.gov/protein/NP_000079.2
MFSFVDLRLLLLLAATALLTHGQEEGQVEGQDEDIPPITCVQNGLRYHDR DVWKPEPCRICVCDNGKVLCDDVICDETKNCPGAEVPEGECCPVCPDGS ESPTDQETTGVEGPKGDTGPRGPRGPAGPPGRDGIPGQPGLPGPPGPPGPP GPPGLGGNFAPQLSYGYDEKSTGGISVPGPMGPSGPRGLPGPPGAPGPQG FQGPPGEPGEPGASGPMGPRGPPGPPGKNGDDGEAGKPGRPGERGPPGP QGARGLPGTAGLPGMKGHRGFSGLDGAKGDAGPAGPKGEPGSPGENGA PGQMGPRGLPGERGRPGAPGPAGARGNDGATGAAGPPGPTGPAGPPGFP GAVGAKGEAGPQGPRGSEGPQGVRGEPGPPGPAGAAGPAGNPGADGQP GAKGANGAPGIAGAPGFPGARGPSGPQGPGGPPGPKGNSGEPGAPGSKG DTGAKGEPGPVGVQGPPGPAGEEGKRGARGEPGPTGLPGPPGERGGPGS RGFPGADGVAGPKGPAGERGSPGPAGPKGSPGEAGRPGEAGLPGAKGLT GSPGSPGPDGKTGPPGPAGQDGRPGPPGPPGARGQAGVMGFPGPKGAAGEPGKAGERGVPGPPGAVGPAGKDGEAGAQGPPGPAGPAGERGEQGPAGSPGFQGLPGPAGPPGEAGKPGEQGVPGD LGAPGPSGARGERGFPGERGVQGPPGPAGPRGANGAPGNDGAKGDAGAPGAPGSQGAPGLQGMPGE RGAAGLPGPKGDRGDAGPKGADGSPGKDGVRGLTGPIGPPGPAGAPGDK GESGPSGPAGPTGARGAPGDRGEPGPPGPAGFAGPPGADGQPGAKGEPG DAGAKGDAGPPGPAGPAGPPGPIGNVGAPGAKGARGSAGPPGATGFPGA AGRVGPPGPSGNAGPPGPPGPAGKEGGKGPRGETGPAGRPGEVGPPGPPG PAGEKGSPGADGPAGAPGTPGPQGIAGQRGVVGLPG QRGERGFPGLPGPSGEPGKQGPSGASGERGPPGPMGPPGLAGPPGESGREGAPGAEGSP GRDGSPGAKGDRGETGPAGPPGAPGAPGAPGPVGPAGKSGDRGETGPAG PAGPVGPVGARGPAGPQGPRGDKGETGEQGDRGIKGHRGFSGLQGPPGP PGSPGEQGPSGASGPAGPRGPPGSAGAPGKDGLNGLPGPIGPPGPRGRTG DAGPVGPPGPPGPPGPPGPPSAGFDFSFLPQPPQEKAHDGGRYYRADDAN VVRDRDLEVDTTLKSLSQQIENIRSPEGSRKNPARTCRDLKMCHSDWKSG EYWIDPNQGCNLDAIKVFCNMETGETCVYPTQPSVAQKNWYISKNPKDK RHVWFGESMTDGFQFEYGGQGSDPADVAIQLTFLRLMSTEASQNITYHC KNSVAYMDQQTGNLKKALLLQGSNEIEIRAEGNSRFTYSVTVDGCTSHTG AWGKTVIEYKTTKTSRLPIIDVAPLDVGAPDQEFGFDVGPVCFL (SEQ ID No.1)
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.1中 的其他序列实现更好的黏附效果。在本发明中，多肽不是SEQ ID No.1的全 长序列。
本发明部分基于以下发现：包含SEQ ID No.1中的至少60个连续的氨基酸 残基的N端区域和以SEQ ID No.2所示的序列GAPGPCCGG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黏附效果，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60-100、72-84等等。
在本发明中，对几种具体的N端区域进行了测试：
(1)GPAGSPGFQGLPGPAGPPGEAGKPGEQGVPGDLGAPGPSGARGER GFPGERGVQGPPGPA(SEQID No.3)；
(2)GEKGSPGADGPAGAPGTPGPQGIAGQRGVVGLPGQRGERGFPGLPGPS GEPGKQGPSGAS(SEQID No.4)；
在本发明中，C端氨基酸序列可以为GAPGPCCGG(SEQ ID No.2)，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C1S4T，为单链结构，包括氨基酸 249个，基本重复单元为 GPAGSPGFQGLPGPAGPPGEAGKPGEQGVPGDLGAPGPSGARGERGFPGE RGVQGPPGPA(SEQ ID No.3)，为人胶原蛋白I型肽段，C端氨基酸序列为 GAPGPCCGG(SEQ ID No.2)，为增强胶原活性的端序列肽段。C1S4T的氨 基酸序列如下： GPAGSPGFQGLPGPAGPPGEAGKPGEQGVPGDLGAPGPSGARGERGFPGE RGVQGPPGPAGPAGSPGFQGLPGPAGPPGEAGKPGEQGVPGDLGAPGPSG ARGERGFPGERGVQGPPGPAGPAGSPGFQGLPGPAGPPGEAGKPGEQGVP GDLGAPGPSGARGERGFPGERGVQGPPGPAGPAGSPGFQGLPGPAGPPGE AGKPGEQGVPGDLGAPGPSGARGERGFPGERGVQGPPGPAGAPGPCCGG (SEQID No.5)。C1S4T的DNA序列如下： GGTCCGGCCGGTAGCCCGGGTTTTCAAGGTCTGCCGGGTCCCGCTGGTCCTCCGGGTGAGGCTGGTAAACCCGGTGAGCAAGGTGTTCCCGGTGAT CTGGGTGCACCGGGTCCGAGTGGTGCACGTGGTGAGCGTGGCTTTCCG GGTGAGCGTGGCGTTCAAGGTCCCCCCGGTCCGGCTGGTCCGGCTGGT AGTCCCGGTTTCCAAGGTCTGCCCGGTCCCGCTGGTCCTCCGGGTGAA GCCGGTAAACCGGGCGAGCAAGGTGTTCCGGGTGATTTAGGTGCCCCC GGTCCGAGCGGTGCACGTGGTGAGCGCGGCTTCCCGGGTGAACGCGG TGTTCAAGGTCCCCCCGGTCCGGCTGGTCCCGCTGGTAGTCCGGGTTT CCAAGGTTTACCCGGTCCGGCTGGTCCCCCCGGTGAAGCTGGTAAACC GGGTGAACAAGGTGTTCCGGGTGATTTAGGCGCACCCGGTCCTAGCGG TGCACGTGGTGAGCGTGGCTTCCCGGGTGAACGTGGTGTTCAAGGTCC GCCCGGTCCCGCTGGTCCGGCTGGTAGCCCCGGTTTCCAAGGTCTGCC GGGTCCGGCTGGTCCTCCGGGCGAAGCTGGTAAGCCGGGTGAGCAAG GTGTGCCGGGTGACTTAGGTGCACCGGGTCCGAGTGGTGCACGTGGC GAGCGTGGTTTTCCGGGCGAACGTGGTGTTCAAGGTCCGCCGGGTCCGGCCGGTGCACCGGGTCCGTGTTGTGGTGGT(SEQ ID No.7)。
多肽在本文中可以是人源胶原蛋白C1S5T，为单链结构，包括249个氨基 酸，基本重复单元为 GEKGSPGADGPAGAPGTPGPQGIAGQRGVVGLPGQRGERGFPGLPGPSG EPGKQGPSGAS(SEQID No.4)，为人胶原蛋白I型肽段，C端氨基酸序列 为GAPGPCCGG(SEQ ID No.2)，为增强胶原活性的端序列肽段。C1S5T的 氨基酸序列如下： GEKGSPGADGPAGAPGTPGPQGIAGQRGVVGLPGQRGERGFPGLPGPSG EPGKQGPSGASGEKGSPGADGPAGAPGTPGPQGIAGQRGVVGLPGQRGE RGFPGLPGPSGEPGKQGPSGASGEKGSPGADGPAGAPGTPGPQGIAGQRG VVGLPGQRGERGFPGLPGPSGEPGKQGPSGASGEKGSPGADGPAGAPGTP GPQGIAGQRGVVGLPGQRGERGFPGLPGPSGEPGKQGPSGASGAPGPCC GG(SEQ IDNo.6)。C1S5T的DNA序列如下： GGTGAAAAAGGCAGCCCGGGTGCCGATGGTCCCGCTGGTGCACCGGG TACACCGGGTCCTCAAGGTATTGCCGGTCAACGTGGTGTTGTGGGTCT GCCGGGTCAGCGTGGTGAACGCGGTTTTCCGGGTCTGCCGGGTCCGA GTGGTGAACCGGGTAAACAAGGTCCGAGCGGTGCCAGTGGTGAAAAA GGTAGCCCGGGTGCAGACGGTCCCGCTGGTGCCCCCGGTACACCGGGT CCTCAAGGCATTGCTGGTCAGCGTGGCGTTGTGGGTCTGCCCGGTCAG CGTGGCGAGCGTGGTTTTCCCGGTTTACCCGGTCCGAGTGGCGAGCCC GGTAAGCAAGGTCCGAGTGGTGCCAGCGGTGAGAAGGGTAGTCCGGG TGCAGACGGTCCCGCTGGTGCCCCCGGTACCCCGGGTCCGCAAGGTAT TGCTGGTCAACGTGGTGTTGTTGGTTTACCGGGTCAGCGCGGCGAACG TGGTTTCCCGGGTCTGCCCGGTCCGAGTGGCGAGCCGGGTAAGCAAG GTCCGAGCGGCGCAAGCGGCGAAAAAGGTAGTCCGGGTGCAGATGGTCCCGCTGGTGCACCGGGTACACCGGGTCCTCAAGGTATCGCTGGTCAG CGCGGTGTTGTTGGTCTGCCGGGTCAACGCGGTGAACGTGGTTTCCCG GGTCTGCCCGGTCCGAGTGGCGAACCGGGTAAACAAGGTCCGAGCGG TGCCAGCGGTGCACCGGGTCCGTGTTGTGGTGGT(SEQ ID No.8)。
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I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。
大肠杆菌仅仅是例示性的。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。
本发明的肽包含以SEQ ID No.5或SEQ ID No.6所示的序列或或以 SEQ ID No.5或SEQ ID No.6所示的序列中取代、缺失、插入和/或添加一 个、两个或多个氨基酸的序列，所述肽显示黏附活性。“多个”可以是2、3、 4、5、6、7、或8个。
氨基酸取代意味着在相同位置，某个氨基酸残基被其他氨基酸残基替 代。插入的氨基酸残基可以在任何位置插入，插入的氨基酸残基也可以全部 或部分彼此相邻，或插入的氨基酸之间都不彼此相邻。可以从SEQ ID NO:1 的序列中删除1、2或3个氨基酸，只要所述肽显示抑制神经细胞的活性或 除皱活性。
本领域技术人员已知，本发明所述的肽可以在氨基酸序列之间的一个或 多个位置进行翻译后修饰。翻译后修饰的例子可以包括磷酸化作用、乙酰化 作用和脱酰氨基作用。
本发明还提供SEQ ID No.5或6所示的肽的类似物，只要类似物显示细 胞黏附活性。这些类似物与天然的肽差别可以是氨基酸序列上的差异，也可 以是不影响序列的修饰形式上的差异，或者兼而有之。这些肽包括天然或诱 导的遗传变异体。诱导变异体可以通过各种技术得到，如通过辐射或暴露于 诱变剂而产生随机诱变，还可通过定点诱变法或其他已知分子生物学的技 术。类似物还包括具有不同于天然L-氨基酸的残基(如D-氨基酸)的类似物， 以及具有非天然存在的或合成的氨基酸(如β、γ-氨基酸)的类似物。
在本发明中，取代可以是保守氨基酸取代，指与SEQ ID NO:5或6的 氨基酸序列相比，有至多3个，更佳地至多2个氨基酸或1个氨基酸被性质 相似或相近的氨基酸所替换而形成肽。这些保守性变异肽可以根据表1进行 氨基酸替换而产生。
| 最初的残基 | 代表性的取代 | 优选的取代 |
| Ala(A) | Val；Leu；Ile | Val |
| Arg(R) | Lys；Gln；Asn | Lys |
| Asn(N) | Gln；His；Lys；Arg | Gln |
| Asp(D) | Glu | Glu |
| Cys(C) | Ser | Ser |
| Gln(Q) | Asn | Asn |
| Glu(E) | Asp | Asp |
| Gly(G) | Pro；Ala | Ala |
| His(H) | Asn；Gln；Lys；Arg | Arg |
| Ile(I) | Leu；Val；Met；Ala；Phe | Leu |
| Leu(L) | Ile；Val；Met；Ala；Phe | Ile |
| Lys(K) | Arg；Gln；Asn | Arg |
| Met(M) | Leu；Phe；Ile | Leu |
| Phe(F) | Leu；Val；Ile；Ala；Tyr | Leu |
| Pro(P) | Ala | Ala |
| Ser(S) | Thr | Thr |
| Thr(T) | Ser | Ser |
| Trp(W) | Tyr；Phe | Tyr |
| Tyr(Y) | Trp；Phe；Thr；Ser | Phe |
| Val(V) | Ile；Leu；Met；Phe；Ala | Leu |
序列同一性：参数“序列同一性”描述两个氨基酸序列之间或两个核苷酸 序列之间的相关性。
就本发明而言，两个氨基酸序列之间的序列同一性程度使用如EMBOSS 软件包(EMBOSS：The European Molecular Biology Open Software Suite，Rice 等，2000，Trends Genet.16：276-277)，优选3.0.0版或更高版本的Needle程序中 所执行的Needleman-Wunsch算法(Needleman和Wunsch，1970，J.Mol.Biol. 48：443-453)来测定。使用的可选参数为缺口罚分(gap penalty)10，缺口延伸罚 分(gap extension penalty)0.5和EBLOSUM62(BLOSUM62的EMBOSS版)取代 矩阵。使用Needle标记为“最高同一性(longestidentity)”的输出结果(使用 -nobrief选项获得)作为同一性百分比，并计算如下：
(同样的残基×100)/(比对长度-比对中缺口的总数)
就本发明而言，杂交表示多核苷酸在非常低至非常高的严格条件下与标 记的核酸探针杂交，所述核酸探针对应于SEQ ID NO：5或6的多肽编码序列。 可使用例如X射线片(X-ray film)检测在这些条件下与核酸探针杂交的分子。
对于长度至少100个核苷酸的长探针，将非常低至非常高的严格条件定 义为在42℃，在5X SSPE、0.3％SDS、200微克/ml已剪切并且变性的鲑精 DNA中，并且对于非常低和低严格性为25％的甲酰胺、对于中和中-高严格 性为35％的甲酰胺、或对于高和非常高严格性为50％的甲酰胺，根据标准的 Southern印迹法进行预杂交和杂交最佳12至24小时。使用2X SSC、0.2％SDS 至少在45℃(非常低严格性)，至少在50℃(低严格性)，至少在55℃(中严格性)， 至少在60℃(中-高严格性)，至少在65℃(高严格性)，至少在70℃(非常高严格 性)将载体材料最终洗涤三次，每次15分钟。
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
C1S4T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C1S4T全长基因序列以SEQ ID No.7 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.C1S4T基因全长747bp，根据优化后的C1S4T密码子基因序列SEQ ID No.7，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 C1S4T基因片段通过BamHI(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 NaH2PO3，500mM 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)(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C1S4T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。
C1S5T基因表达载体的构建及表达
1.人源胶原蛋白C1S5T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.C1S5T基因全长747bp，根据优化后的C1S5T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C1S5T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C1S5T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。
结果
图2和图3的电泳图表明得到表观分子量为36kDa的C1S4T和C1S5T，分 子量分别对应于SEQ ID NO:5和6的氨基酸序列的多肽，表明多肽C1S4T和 C1S5T得到正确表达。
实施例2C1S4T和C1S5T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)、C1S4T和C1S5T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.Humana Press.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4和图5。
图4和图5的结果表明，两种人重组胶原蛋白(即C1S4T和C1S5T)与商品 化的人胶原蛋白相比，皆具有相当或更好的黏附活性。本发明的重组I型胶 原蛋白C1S4T和C1S5T实现了I型胶原蛋白的细胞黏附活性。
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Asp Gly Pro Ala Gly Ala Pro Gly Thr Pro Gly Pro Gln Gly Ile Ala
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<210> 7
<211> 747
<212> DNA
<213> 人工序列
<220>
<223> C1S4T的DNA序列
<400> 7
ggtccggccg gtagcccggg ttttcaaggt ctgccgggtc ccgctggtcc tccgggtgag 60
gctggtaaac ccggtgagca aggtgttccc ggtgatctgg gtgcaccggg tccgagtggt 120
gcacgtggtg agcgtggctt tccgggtgag cgtggcgttc aaggtccccc cggtccggct 180
ggtccggctg gtagtcccgg tttccaaggt ctgcccggtc ccgctggtcc tccgggtgaa 240
gccggtaaac cgggcgagca aggtgttccg ggtgatttag gtgcccccgg tccgagcggt 300
gcacgtggtg agcgcggctt cccgggtgaa cgcggtgttc aaggtccccc cggtccggct 360
ggtcccgctg gtagtccggg tttccaaggt ttacccggtc cggctggtcc ccccggtgaa 420
gctggtaaac cgggtgaaca aggtgttccg ggtgatttag gcgcacccgg tcctagcggt 480
gcacgtggtg agcgtggctt cccgggtgaa cgtggtgttc aaggtccgcc cggtcccgct 540
ggtccggctg gtagccccgg tttccaaggt ctgccgggtc cggctggtcc tccgggcgaa 600
gctggtaagc cgggtgagca aggtgtgccg ggtgacttag gtgcaccggg tccgagtggt 660
gcacgtggcg agcgtggttt tccgggcgaa cgtggtgttc aaggtccgcc gggtccggcc 720
ggtgcaccgg gtccgtgttg tggtggt 747
<210> 8
<211> 747
<212> DNA
<213> 人工序列
<220>
<223> C1S5T的DNA序列
<400> 8
ggtgaaaaag gcagcccggg tgccgatggt cccgctggtg caccgggtac accgggtcct 60
caaggtattg ccggtcaacg tggtgttgtg ggtctgccgg gtcagcgtgg tgaacgcggt 120
tttccgggtc tgccgggtcc gagtggtgaa ccgggtaaac aaggtccgag cggtgccagt 180
ggtgaaaaag gtagcccggg tgcagacggt cccgctggtg cccccggtac accgggtcct 240
caaggcattg ctggtcagcg tggcgttgtg ggtctgcccg gtcagcgtgg cgagcgtggt 300
tttcccggtt tacccggtcc gagtggcgag cccggtaagc aaggtccgag tggtgccagc 360
ggtgagaagg gtagtccggg tgcagacggt cccgctggtg cccccggtac cccgggtccg 420
caaggtattg ctggtcaacg tggtgttgtt ggtttaccgg gtcagcgcgg cgaacgtggt 480
ttcccgggtc tgcccggtcc gagtggcgag ccgggtaagc aaggtccgag cggcgcaagc 540
ggcgaaaaag gtagtccggg tgcagatggt cccgctggtg caccgggtac accgggtcct 600
caaggtatcg ctggtcagcg cggtgttgtt ggtctgccgg gtcaacgcgg tgaacgtggt 660
ttcccgggtc tgcccggtcc gagtggcgaa ccgggtaaac aaggtccgag cggtgccagc 720
ggtgcaccgg gtccgtgttg tggtggt 747
Claims (12)
1.多肽，所述多肽由以SEQ ID No. 5或SEQ ID No. 6所示的氨基酸序列组成。
2.多核苷酸，其编码根据权利要求1所述的多肽。
3.表达载体，其包含根据权利要求2所述的多核苷酸。
4.宿主细胞，其包含根据权利要求3所述的表达载体。
5.根据权利要求4所述的宿主细胞，其中所述宿主细胞是大肠杆菌。
6.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4或5所述的宿主细胞并生产多肽；和
(2) 收获并纯化多肽。
7.根据权利要求6所述的生产方法，所述方法包括对多肽进行酶切的步骤。
8.组合物，其包含根据权利要求1所述的多肽。
9.根据权利要求8所述的组合物，其中所述组合物是医疗器材、组织工程产品、化妆品或保健品。
10.根据权利要求1所述的多肽在制备组合物中的用途。
11.根据权利要求10所述的用途，其中所述组合物是医疗器材、组织工程产品、化妆品或保健品。
12.根据权利要求1所述的多肽在制备用于促进细胞黏附的药物中的用途。
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| CN109988234A (zh) * | 2019-02-20 | 2019-07-09 | 江苏悦智生物医药有限公司 | 酵母重组人源I型胶原α1链蛋白、合成方法及其应用 |
| 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 |
| 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 |
| CN113683681B (zh) * | 2021-09-15 | 2023-10-03 | 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c1l3t及其制备方法和用途 |
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| 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 |
| 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 |
| CN113683678B (zh) * | 2021-09-15 | 2023-11-24 | 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c1l2t及其制备方法和用途 |
| CN114316030B (zh) * | 2022-01-27 | 2023-06-30 | 西安巨子生物基因技术股份有限公司 | 一种透皮吸收性的i型重组胶原蛋白及其用途 |
| CN116813793A (zh) * | 2022-05-13 | 2023-09-29 | 山西锦波生物医药股份有限公司 | 融合蛋白以及其应用 |
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| CN116715754B (zh) * | 2023-05-12 | 2024-03-12 | 山西锦波生物医药股份有限公司 | 多肽及其用途 |
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