Most peptides target extracellular molecules
The extracellular molecular target is mainly G protein coupled receptor (GPCR). GPCR family is the largest receptor family, and about 800-1000 members have been identified. GPCR plays an extremely important role in the development of modern medicine. About 50% of modern medicine is targeted at GPCR. All of these GPCRs have seven transmembrane domains. GPCR signal generally interacts with these GPCRs through extracellular ligands, causing conformational changes of GPCR, and regulating various signal pathways downstream of GPCR by activating triplet G protein. Some receptors of GPCR family are abnormally expressed in specific tissues and cells, regulating normal or abnormal physiological functions of human body, which are potential targets of drug development. Some GPCR ligands are small peptides, and the modification of these peptides has become one of the most important directions in peptide drug development.
Less than 10% target intracellular molecules
1、 Preparation of polypeptide drugs
Extraction method
A considerable part of polypeptide drugs are extracted from plants, such as insulin from the pancreas of pigs. The purity of polypeptide obtained by extraction method is low, and the content of polypeptide in organism is very small, so it is easy to introduce animal pathogenic bacteria or virus in the extraction process, which limits its application. Therefore, biological peptide extraction technology has been gradually replaced by chemical synthesis or gene recombination technology.
Chemical synthesis
(1) Protective agents for peptide synthesis
Polypeptides are composed of amino acids. Whether they are natural polypeptides or synthetic polypeptides, there are different amino acids connected by amide bonds in a certain order. The amide bond is formed by the removal of one amino acid’s amino group from the carboxyl group of another amino acid. Therefore, the chemical synthesis of polypeptides focuses on the activation or protection of amino and carboxyl groups at the right place and time. The synthesis of polypeptide includes three steps: Step 1, protect the active part which does not participate in the reaction; step 2, activate the carboxyl group as the active intermediate; step 3, deprotect the protected group. The peptide was purified by HPLC.
(2) Liquid phase synthesis of polypeptide drugs
The liquid-phase synthesis of polypeptide is mainly carried out in solution, and there are two strategies: Step-by-Step synthesis and fragment combination. These two strategies are often used in combination. First, some short peptide fragments were synthesized by step synthesis. The peptide fragment obtained in the previous step is then connected to the target peptide by the method of fragment combination. The method of liquid phase synthesis is convenient and high purity, which is suitable for the situation of short target polypeptide and large amount of synthesis.
(3) Solid phase synthesis of polypeptide drugs
The N-terminal of amino acids is fixed on the insoluble resin, and then the amino acids are condensed successively on the resin. Solid phase method has become a common technology in peptide and protein synthesis. Especially in the synthesis of long-chain polypeptide or protein, the solid-phase synthesis method shows the advantages that the classical liquid-phase synthesis method can not compare.
Gene recombination technology
Many living things in nature can produce active peptides, such as insulin in mammals. However, the extraction of active polypeptides from driven plants needs a lot of raw materials, which is expensive and not green enough. Using gene technology to produce natural active polypeptides solves this problem. Recombinant technology is to construct the gene sequence of polypeptide on the vector to form recombinant DNA expression vector, and to express, extract and purify polypeptide molecules in prokaryotic or eukaryotic cells. This method is suitable for the preparation of target peptides with more than 50 amino acids and is easy to obtain. With the improvement of the technology of peptide production by genetic engineering, the development and clinical application of peptide drugs by genetic engineering have been accelerated.
Preparation of polypeptide drugs by enzymatic degradation [4]
Organisms contain a large number of proteins, some active peptides may be a certain sequence in the protein, if the relatively easy protein can be degraded into the required peptide molecules (may be many), it can also play a cost saving effect. In recent years, some scholars have used enzymolysis to synthesize peptides. Enzyme degradation often needs to find the enzyme that catalyzes the decomposition reaction at a specific structure. It can efficiently play a role in all the same structures of proteins. However, it is difficult to separate and purify a series of peptides, so it is not suitable to synthesize a single peptide. In addition, due to the strong specificity of enzymes, sometimes it is necessary to cut off multiple structural units, then it is necessary to find a variety of enzymes, which increases the application difficulty and scope of the method.
2、 Detection of polypeptide drugs
Reversed phase high performance liquid chromatography
High performance liquid chromatography (HPLC) has become the most commonly used method in drug quality analysis, which is sensitive, accurate and fast. Polypeptide substances are made up of several amino acids connected by peptide bond, with certain hydrophobicity, certain retention on reversed-phase chromatographic column, and can be effectively separated in reversed-phase HPLC. Now, the analysis of polypeptide drugs is mostly used High performance liquid chromatography.
capillary electrophoresis
In addition to the traditional high-performance liquid chromatography for the analysis of related substances, capillary electrophoresis also has great advantages in the analysis of polypeptide drugs. Capillary electrophoresis has the advantages of high-pressure electrophoresis and liquid chromatography. Different from the separation mechanism of hydrophobicity of reversed-phase high-performance liquid chromatography, there are many separation modes, with fast analysis speed and high resolution, which are used for samples It is characterized by less quantity, simple operation and less consumption.
High performance liquid chromatography mass spectrometry
Liquid chromatography-mass spectrometry (LC-MS) has become an important method for the separation and identification of various compounds. MS is a powerful tool for structural analysis, which can provide more information for structural characterization. As an ideal chromatographic detector, MS has not only strong specificity, but also high detection sensitivity. When liquid chromatography-mass spectrometry (LC-MS) is used for the analysis of related substances of polypeptide drugs, the information of first-order or even multi-stage mass spectrometry of impurities can be given without obtaining pure impurities, so as to obtain the molecular weight and sequence information of the heteropeptide and provide the basis for the qualitative and structural analysis of related peptides.
High performance molecular exclusion chromatography
High performance molecular chromatography is a kind of liquid chromatography technology which is based on the size of molecules. It is commonly used in the determination of molecular weight of protein polypeptide, biomacromolecule polymer and molecular weight distribution, and the determination of high molecular impurities in drugs.
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