A comprehensive picture of non‐site specific oxidation of methionine residues by peroxides in protein pharmaceuticals

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. © 2004 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:3096–3102, 2004