生物体内的多种生命进程调节都是通过蛋白质与蛋白质之间的相互作用来实现的。例如病毒的自组装,细胞的生长,分裂,分化等过程。而通常蛋白-蛋白相互作用的界面太大,从而使小分子药物很难对其进行靶向定位,达到高效特异性地阻断这种相互作用,展现良好的治疗效果。蛋白类药物因为很难顺利通过细胞膜所以也达不到直接靶向细胞内相互作用的效果,因此,研究者们开始寻求一种能够克服这两种药物缺点的既能够进入细胞膜又能特异性靶向蛋白-蛋白相互作用的新的药物分子。
研究表明,具有α-螺旋结构和富含正电荷的多肽可以穿过细胞膜。但是一旦从母体分离就不能保持其原有的二级结构,构象的不稳定导致其与蛋白质的结合作用减弱,而普通的线性多肽不能穿过细胞膜且容易被水解。经过不断尝试,Verdine等发展了一种新型结构的多肽,这种多肽被称为订书肽,它是一种全碳支架的具有α-螺旋结构的多肽,全碳支架稳定α-螺旋结构,增强了多肽分子与蛋白质的相互作用,并且订书肽能够穿过细胞膜,不容易被水解,相比于之前的小分子药物和蛋白类药物,具有更高的药理活性。
订书肽的合成与普通多肽合成的区别在于在固相合成肽链过程中引入两个含有α-甲基,α-烯基的非天然氨基酸,然后两个非天然氨基酸之间发生烯烃复分解反应环化构成稳定α-螺旋结构构象的全碳支架,进而合成订书肽。
上图为两种不同构型的含有α-甲基,α-烯基的非天然氨基酸的一般结构。这种类型的氨基酸合成方法一般为:
订书肽的一般合成路线为:
国肽生物始终坚持客户至上的经营理念,通过长久的实验累积,不断优化合成条件和纯化工艺,已经具备了成熟的订书肽合成工艺,具有了向全球提供高品质的订书多肽的能力,能够充分满足客户的各种研发需要。
成功案例:
合成下列结构订书肽
HPLC分析:
MS分析:
合肥国肽生物官网:http://www.bankpeptide.com
翻译:
translation:
The regulation of multiple life processes in an organism is achieved through the interaction between proteins and proteins. For example, self-assembly of viruses, cell growth, division, differentiation and the like. Usually, the interface of protein-protein interaction is too large, so that it is difficult for small molecule drugs to target them, and the interaction is effectively and specifically blocked, showing good therapeutic effects. Because protein drugs are difficult to pass through the cell membrane, they do not directly target intracellular interactions. Therefore, researchers have begun to seek a solution that can overcome the shortcomings of these two drugs and enter the cell membrane and specific targets. A new drug molecule that interacts with protein-proteins.
Studies have shown that polypeptides with alpha-helical structures and positively charged can cross cell membranes. However, once it is separated from the mother, its original secondary structure cannot be maintained. The instability of the conformation causes its binding to proteins to be weakened, while the ordinary linear polypeptide cannot pass through the cell membrane and is easily hydrolyzed. After repeated attempts, Verdine et al. developed a novel structure of a peptide called a staple peptide, which is an all-carbon scaffold with an α-helical structure and an all-carbon scaffold that stabilizes the α-helical structure. The interaction between the polypeptide molecule and the protein is enhanced, and the peptide can pass through the cell membrane and is not easily hydrolyzed, and has higher pharmacological activity than the previous small molecule drugs and protein drugs.
The synthesis of a peptide is different from the synthesis of a common polypeptide by introducing two unnatural amino acids containing an α-methyl group, an α-alkenyl group, and then an olefin metathesis reaction between two unnatural amino acids. Cyclization constitutes a full carbon scaffold that stabilizes the conformation of the α-helical structure, thereby synthesizing the book peptide.
The top panel shows the general structure of an unnatural amino acid containing alpha-methyl, alpha-alkenyl groups in two different configurations. This type of amino acid synthesis is generally:
The general synthetic route for a peptide is:
National Peptide Biotechnology always adheres to the customer-oriented business philosophy. Through long-term experimental accumulation, continuous optimization of synthesis conditions and purification processes, it has a mature synthesis process of peptides, and has the ability to provide high-quality peptides to the world. Can fully meet the various research and development needs of customers.
success case:
Synthesis of the following structural peptides
HPLC analysis:
MS analysis:
Bankpeptide biological technology co.,LTD:http://www.bankpeptide.com