PEGylated protein

The N-terminal methionine residue of protein can also be employed for selective PEGylation using aldehyde-terminated PEG via a reductive amination reaction, because the N-terminal primary amine has a lower pAa of 7.8 than other amines such as lysines, whose pZa is 10.1 [7]. After reaction with aldehyde-terminated PEG at low pH, the resultant imine is reduced with sodium cyanoborohydrate to provide PEGylated protein (Fig. 4) [8, 9]. This technique was used for the production of Neulasta, which was approved for use by the FDA in 2002 [10]. 

Fig. 4 PEGylation at the N-terminal methionine residue. The difference in pKa. between the N-terminal amine and other amines in the protein enables site-specific PEGylation. After reaction with aldehyde-terminated PEG at low pH, reduction of the resultant imine produces PEGylated protein...

Although the detailed mechanism of the longer circulation time of branched PEGylated protein is unclear, the architecture of PEG affects the release profile, the pharmacokinetics of the chug [29], and the behavior of the protein at the interface (e.g., protein absorption on hydrophobic surfaces [30]). 

Siegel, N., Stadler, J., Tilbury, L. and Smith, D. (2007) PEGylated proteins evaluation of their safety in the absence of definitive metabolism studies. Drug Metab. Dispos., 35 (1), 9-16. 

Integration of Pharmacokinetics and Pharmacodynamics Into the Drug Development of Pegfilgrastim, a Pegylated Protein... 

Heller, M., Carpenter, )., Randolph, T., Conformational stability of lyophilized PEGylated proteins in a phase-separating system, J. Pharmac. Sci. 88, 58-64, 1999. 

Anytime the term process chemist is used, it usually relates to the development of a small synthetic molecule. However, there has been a growth explosion in the development of macromolecules as of late. These may include proteins, small molecules attached to proteins, pegylated proteins, DNA and RNA fragments, oligonucleotides, monoclonal antibodies, and even personalized medicines in vaccines being made from a specific patient to treat the same patient. As this is a growing trend within the pharmaceutical industry, the term process chemist should include development chemists who are involved in all of the above-mentioned areas. A major difference between these areas and the development of small molecules is that the process to manufacture these complex products usually defines the product versus the other way around for small molecules, where the product defines the process. 

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