Chemical modification of proteins has a long history. From the beginning of the study of protein structure, biochemists have used various chemical methods to modify the amino acid side chain groups of proteins, such as sulfhydryl, amino, imidazolyl, guanidino, and indolyl groups, and connect various chemical groups to investigate protein structure and Changes in functionality. When the enzyme was modified, the measured catalytic activity decreased, even greatly. From this point of view, some people hold a negative attitude towards PEG modification.
Although modifications can reduce the immunogenicity of the protein, the dramatic decrease in biological activity often makes further explorations forgoing. However, when the modified proteins were injected into animals and their in vivo biological activity was measured, they found that the biological activity in vivo was unexpectedly high and sustained for a long time. The discovery has excited biotech companies, as they can use the technology to develop long-acting genetically engineered protein drugs. Low in vitro activity and high in vivo activity have become a common phenomenon of PEG-modified proteins, which many people have not thought of before.
Through further research, it was found that the increase in in vivo activity is related to the molecular weight of PEG: the increase in molecular weight can usually increase the half-life (or half-life) of the drug in the body, thus promoting polyethylene glycol manufacturers to synthesize higher molecular weight mPEG, from 10,000 to 20,000, 30,000 or even 40,000. Branched PEG was also synthesized and showed better in vivo half-life extension than linear PEG of the same molecular weight.
So far, the half-life of the polyethylene glycol-modified protein drugs on the market has been increased by several times more than the original drug. The use of the drug has been changed from 1 injection per day to 1 injection per week, which greatly facilitates the patients and improves the drug use. effect. For example, polyethylene glycol-modified interferon is used to treat hepatitis C, and its effect is better than that of unmodified interferon. Therefore, polyethylene glycol modification has been developed from the original intention of overcoming immunogenicity to the main means to prolong the efficacy and improve the therapeutic effect.