兰州大学机构库 >生命科学学院
多肽药物—胸腺肽α1与鲑鱼降钙素合成工艺研究
Alternative TitleStudy on the Synthesis Process of Peptide drugs—Thymosin α1 and Salmon calcitonin
薛宏祥
Thesis Advisor彭雅丽
2015-05-24
Degree Grantor兰州大学
Place of Conferral兰州
Degree Name硕士
Keyword胸腺肽α1 乙型肝炎 鲑鱼降钙素 骨质疏松症 裂解 反向高效液相色谱 反向高效液相色谱
Abstract胸腺肽α1(又称胸腺法新,胸腺素α1,Thymosinal,Tα1),含有28个氨基酸的多肽活性药物,它是由前胸腺素经过天冬酰胺内肽酶裂解之后形成的产物,主要存在于胸腺中。胸腺肽α1在免疫调节、内分泌以及中枢神经系统中具有重要作用。胸腺肽α1在临床上主要用于治疗慢性乙肝、丙肝、肿瘤以及免疫缺陷病的治疗。目前胸腺肽α1的合成主要有液相合成、全固相合成以及基因工程合成。在本文中,我们采用固液相结合片段缩合法合成胸腺肽α1。首先将胸腺肽α1 28个氨基酸序列分成若干个片段,固相合成各个全保护片段,然后在液相中将各个全保护片段连接在一起,形成全保护的胸腺肽α1粗肽,粗肽经裂解、反相高效液相色谱(RP-HPLC)纯化得到胸腺肽α1纯肽。通过片段缩合法合成胸腺肽α1,避免了全固相合成过程中12位以后氨基酸缩合困难以及肽链间易形成二级结构的难题;同时比全液相合成耗时短、成本低、肽产率以及粗肽纯度高,非常有利于工业化生产。 鲑鱼降钙素是由32个氨基酸组成的多肽活性化合物,其 N端第1位与第7位氨基酸之间形成一对二硫键,C端以酰胺结尾。临床上主要用于骨质疏松的治疗。目前鲑鱼降钙素的合成方法主要有基因重组以及全固相合成。本文中,我们采用固液相结合的方式进行鲑鱼降钙素的合成。首先我们将整条序列中的32个氨基酸分为3个到4个肽片段,然后固相合成各个全保护的肽片段,液相中分别将各个全保护肽片段偶联起来,从而得到全保护的鲑鱼降钙素粗肽;经过裂解、RP-HPLC纯化,最终得到鲑鱼降钙素纯肽。我们使用固液相结合法合成鲑鱼降钙素,纯肽的收率以及纯度都得到了很大的提高,有利于大规模生产。
Other AbstractThymosin α1(also known as Talpha 1 or Thymalfasin), a 28 amino acid polypeptide active drug, is produced by prothymosin after peptidase cleavage asparagine within the form, and mainly exists in the thymus. Thymosin α1 plays an important role in regulating immune, endocrine and central nervous system. Thymosin α1 has been used for the treatment of chronic hepatitis B, hepatitis C and immuno deficiency diseases in clinic. The manufacturing methods of synthetic Thymosin α1 mainly include solution phase synthesis, gene recombinant and full solid phase peptide synthesis. In this dissertation, a combination of both solution-and solid-phase peptide synthesis employed in the synthesis of Thymosin α1. We divided 28 amino acids sequence into several segments. firstly, we synthetize each fully protected fragment using the solid phase synthesis method, and then coupled each fully protected fragment together in the solution phase, so that forming a full protection Thymosin α1 crude peptide.After cleaved Thymosin α1 crude peptide, crude peptide was further purified by reversed phase high-performance liquid chromatography (RP-HPLC).Finally we obtained pure Thymosin α1. Convergent peptide synthesis can successfully avoid the problems that it is difficult and incomplete to condensation after twelve amino acid coupled, while easy to forming the β- structure in SPPS. Futher more, it also has the following advantages, including low cost, high yield of crude peptide and high purity of the crude peptide. Futher more, it also has the following advantages, including low cost, high yield and high purity of crude peptide, and very suitability for industrial production. Salmon calcitonin is a biologically active peptide consisting of 32 amino acids, between the N-terminal first and seventh amino acid form a pair of two disulfide, C-terminal is amide bond. Clinical is used mainly for the long-term therapy of osteoporosis. At present, synthesis of salmon calcitonin is focused on gene recombination and full solid phase synthesis. In this dissertation, we first synthetize calcitonin salmon by solid-liquid combined manner. Primarily, we divided 32 amino acid sequence into 3 or 4 peptide fragments in the whole experiment, and then we synthetize these fully protected peptide fragments in SPPS. Further, we coupled up these fully protected peptide fragments in the liquid phase, so as to obtain the full protection Salmon calcitonin crude peptide, after cleaved and HPLC purificati...
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Language中文
Document Type学位论文
Identifierhttps://ir.lzu.edu.cn/handle/262010/221509
Collection生命科学学院
Recommended Citation
GB/T 7714
薛宏祥. 多肽药物—胸腺肽α1与鲑鱼降钙素合成工艺研究[D]. 兰州. 兰州大学,2015.
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