A comprehensive picture of non-site specific oxidation of methionine residues by peroxides in protein pharmaceuticals
✍ Scribed by Jhih-Wei Chu; Jin Yin; Bernard R. Brooks; Daniel I.C. Wang; Margaret Speed Ricci; David N. Brems; Bernhardt L. Trout
- Publisher
- John Wiley and Sons
- Year
- 2004
- Tongue
- English
- Weight
- 161 KB
- Volume
- 93
- Category
- Article
- ISSN
- 0022-3549
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✦ Synopsis
In this article, a comprehensive picture of the oxidation of protein pharmaceuticals by peroxides is developed based on our earlier computational and experimental studies. We propose a new mechanism, the water-mediated mechanism, for the oxidation of methionine residues, and it has been shown to satisfy all available experimental data including new data reported here. Based on the water-mediated mechanism, we found a structural property, average 2-shell water coordination number, that correlates well to the relative rates of oxidation of methionine groups. We used this to study the oxidation of granulocyte colony-stimulating factor (G-CSF) and 1-34 human parathyroid hormone hPTH(1-34). We believe that this comprehensive picture should aid researchers in the pharmaceutical sciences to develop solvent formulations for therapeutic proteins in a more rational way.