PEG modification is an important process for increasing the efficacy of a polypeptide or protein in therapeutic or biotechnological aspects. When PEG is attached to a protein or polypeptide in an appropriate manner, it can alter many of the characteristics, while major biologically active functions, such as enzymatic activity or specific binding sites, can be retained.
PEG modification improves the performance of the drug by several ways. First, PEG is attached to the surface of a protein or polypeptide, increasing its molecular size, and it can carry a large amount of water molecules, a PEG-protein is thus increased by 5 to 10 times. Secondly, PEG modification makes the previously insoluble protein not only easy to dissolve, but also highly mobile. In addition, PEG modification can reduce the renal filtration of the drug, reduce its pyrogenicity, reduce the digestion of the protease, and improve its delivery by protecting the molecule from the immune system. At the same time, because it evades the body's defense mechanism, it stays longer at the site of action and increases the local drug concentration.
Significance of PEG modification of GLP-1
GLP-1 is a peptide hormone of 30 amino acids in length. Usually, peptide hormones of this length are orally ineffective, requiring injection or other suitable peptide drugs (eg, pulmonary or buccal administration) similar to glucagon, and GLP-1 is prone to form. Fiber, so it is very difficult to dissolve in water. Recently, there have been many reports that GLP-1 is difficult to form a mixture and it is difficult to form a drug. The pharmacokinetic properties of GLP-1 have made this problem even greater. Dipeptidase IV rapidly degrades GLP-1, and its product is not only inactive, but also acts as an antagonist of the GLP-1 receptor, producing the opposite effect. At the same time, glomerular filtration of GLP-1 is very rapid. For the above reasons, the half-life of GLP-1 in humans is very short, only 1.5 minutes for intravenous injection and 1.5 hours for subcutaneous injection, which is not suitable for use as a drug. In response to the above deficiencies, the modification of GLP-1 has become a research hotspot. The GLP-1 developed by Novo Nordisk A/S, which is now in clinical use, has been fatty acid-modified, with good viability and a half-life of more than 12 hours. It can be administered once or twice daily. The use of PEG modification not only achieves the same effect, but also avoids patent disputes, and the PEG modification technology is more mature, and the raw materials of the modification are more readily available.
In addition, technically, Lys is the site of choice for most PEG modifications, and many types of PEG are available. GLP-1 has two Lys and is in a non-viable area, thus providing great flexibility for modification.
PEG chemistry
Modifications of the polypeptide include determination of the size of the PEG, determination of the type of activation, and acquisition of activated PEG; acquisition of the polypeptide; determination of the polypeptide modification site, protection of the reactive group, control of the linkage reaction conditions, and characterization of the product. Also included are assays for activity and half-life determination of polypeptide modifications.
Preliminary determination of reaction sites
For the polypeptide, it is divided into a reaction group of a thiol group, an amino group and the like according to the reaction type, and a reaction with a carboxyl group. The reactive groups acting as nucleophiles in the reaction are (depending on the size of the activity): mercapto, alpha-amino, epsilon-amino, carboxylate and hydroxyl. This order is not absolute and is related to other factors such as pH. Sulfhydryl groups are rare in protein and are often associated with active sites and are not suitable as sites for PEG binding. While the carboxylate activity is not high, the amino group is a common group for PEG modification. However, there are exceptions. If the amino group has a great influence on the activity of the polypeptide, then the carboxyl group is selected as the binding site. Therefore, which group to choose as the binding site should be considered according to the specific conditions of the peptide.
PEG modification improves the performance of the drug by several ways. First, PEG is attached to the surface of a protein or polypeptide, increasing its molecular size, and it can carry a large amount of water molecules, a PEG-protein is thus increased by 5 to 10 times. Secondly, PEG modification makes the previously insoluble protein not only easy to dissolve, but also highly mobile. In addition, PEG modification can reduce the renal filtration of the drug, reduce its pyrogenicity, reduce the digestion of the protease, and improve its delivery by protecting the molecule from the immune system. At the same time, because it evades the body's defense mechanism, it stays longer at the site of action and increases the local drug concentration.
Significance of PEG modification of GLP-1
GLP-1 is a peptide hormone of 30 amino acids in length. Usually, peptide hormones of this length are orally ineffective, requiring injection or other suitable peptide drugs (eg, pulmonary or buccal administration) similar to glucagon, and GLP-1 is prone to form. Fiber, so it is very difficult to dissolve in water. Recently, there have been many reports that GLP-1 is difficult to form a mixture and it is difficult to form a drug. The pharmacokinetic properties of GLP-1 have made this problem even greater. Dipeptidase IV rapidly degrades GLP-1, and its product is not only inactive, but also acts as an antagonist of the GLP-1 receptor, producing the opposite effect. At the same time, glomerular filtration of GLP-1 is very rapid. For the above reasons, the half-life of GLP-1 in humans is very short, only 1.5 minutes for intravenous injection and 1.5 hours for subcutaneous injection, which is not suitable for use as a drug. In response to the above deficiencies, the modification of GLP-1 has become a research hotspot. The GLP-1 developed by Novo Nordisk A/S, which is now in clinical use, has been fatty acid-modified, with good viability and a half-life of more than 12 hours. It can be administered once or twice daily. The use of PEG modification not only achieves the same effect, but also avoids patent disputes, and the PEG modification technology is more mature, and the raw materials of the modification are more readily available.
In addition, technically, Lys is the site of choice for most PEG modifications, and many types of PEG are available. GLP-1 has two Lys and is in a non-viable area, thus providing great flexibility for modification.
PEG chemistry
Modifications of the polypeptide include determination of the size of the PEG, determination of the type of activation, and acquisition of activated PEG; acquisition of the polypeptide; determination of the polypeptide modification site, protection of the reactive group, control of the linkage reaction conditions, and characterization of the product. Also included are assays for activity and half-life determination of polypeptide modifications.
Preliminary determination of reaction sites
For the polypeptide, it is divided into a reaction group of a thiol group, an amino group and the like according to the reaction type, and a reaction with a carboxyl group. The reactive groups acting as nucleophiles in the reaction are (depending on the size of the activity): mercapto, alpha-amino, epsilon-amino, carboxylate and hydroxyl. This order is not absolute and is related to other factors such as pH. Sulfhydryl groups are rare in protein and are often associated with active sites and are not suitable as sites for PEG binding. While the carboxylate activity is not high, the amino group is a common group for PEG modification. However, there are exceptions. If the amino group has a great influence on the activity of the polypeptide, then the carboxyl group is selected as the binding site. Therefore, which group to choose as the binding site should be considered according to the specific conditions of the peptide.
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