Polyethylene glycol (PEG) is a pH-neutral, non-toxic macromolecular polymer. It is usually soluble in water and various organic solvents, and has a wide range of solubility, good biocompatibility and good stability. Its repeating unit is an oxyethylene group, its end groups are two hydroxyl groups, and it is a linear or branched structure.
PEGylation modification is the process of chemically coupling activated polyethylene glycol to another molecule (usually a peptide or protein). PEGylation modification has the effects of prolonging half-life, reducing immunogenicity, increasing water solubility, reducing toxic side effects and enhancing stability.
Advantages of PEGylation modification
Peptides are biologically active substances with great application potential. However, the modification of small molecule peptides is difficult and the half-life is extremely short. Today, these problems can be solved by applying PEGylation modification technology to peptides.
The PEG group can be coupled with the active group in the peptide molecule, usually with lysine, and sometimes with aspartic acid, glutamic acid, cysteine in free form, serine, threonine, an amine with an N-terminus or a carboxylic acid with a C-terminus is used for coupling. Hydrophilic PEG could improve the overall hydrophilic and hydrophobic properties of the peptide and improve the water solubility of the peptide. In addition, due to the steric hindrance of PEG, the resistance of the modified peptide to protease hydrolysis was greatly improved, and the molecular exclusion volume of the modified molecule was significantly increased, resulting in a significant decrease in renal filtration clearance. The spherical PEG structure protects the peptide and reduces the immunogenicity of foreign peptides by reducing the uptake to dendritic cells. PEG can prolong the circulating half-life of peptides. Due to these effects, the PEGylated peptides have better pharmacokinetic and pharmacodynamic properties than unmodified peptides.
The PEGylation modification of peptides can be carried out on a solid support, which is easy to achieve selective modification of a certain site in the peptide chain. PEGylation modification can also be carried out in aqueous solution, which can realize the modification of peptides with larger molecular weight by PEG with larger molecular weight.
The negative effects of PEGylation modification are also present. The presence of PEG may affect the binding of the peptide to the target receptor. Therefore, it is necessary to find suitable modification sites and carry out PEGylation modification design carefully.
The PEGylation modification sites of peptides are amino, carboxyl and sulfhydryl groups in the peptide chain.
In the PEGylation modification method of peptides, acylation is mainly performed on the amino group on the N-terminal or lysine side chain, or alkylation on the amino group on the N-terminal is performed. The amino group in the peptide chain has high affinity reactivity. There are many types of PEGs used for amino modification.
Carboxyl groups are also common chemical reactive groups on the side chains of peptide molecules. Carboxyl groups can be combined with PEG amino groups.
Because the content of sulfhydryl groups in peptide molecules is not high and the position is determined, all free sulfhydryl groups that have little effect on activity can be quantitatively and site-specifically modified.
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