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

Jhih-Wei Chu, Jin Yin, Bernard R. Brooks, Daniel I.C. Wang, Margaret Speed Ricci, David N. Brems, Bernhardt L. Trout*

*Corresponding author for this work

Research output: Contribution to journalArticle

45 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)3096-3102
Number of pages7
JournalJournal of Pharmaceutical Sciences
Volume93
Issue number12
DOIs
StatePublished - 1 Jan 2004

Keywords

  • Ab initio calculations
  • GCSF
  • hPTH(1-34)
  • Methionine
  • Molecular dynamics
  • Peroxides
  • Protein oxidation

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