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

  1. Jhih-Wei Chu1,
  2. Jin Yin1,
  3. Bernard R. Brooks2,
  4. Daniel I.C. Wang1,
  5. Margaret Speed Ricci3,
  6. David N. Brems3,
  7. Bernhardt L. Trout1,*

Article first published online: 27 OCT 2004

DOI: 10.1002/jps.20207

Issue

Journal of Pharmaceutical Sciences

Journal of Pharmaceutical Sciences

Volume 93, Issue 12, pages 3096–3102, December 2004

Total views since August 2010: 294

Additional Information

How to Cite

Chu, J.-W., Yin, J., Brooks, B. R., Wang, D. I.C., Ricci, M. S., Brems, D. N. and Trout, B. L. (2004), A comprehensive picture of non-site specific oxidation of methionine residues by peroxides in protein pharmaceuticals. J. Pharm. Sci., 93: 3096–3102. doi: 10.1002/jps.20207

Author Information

  1. 1

    Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139

  2. 2

    Laboratory of Structural Biology, Division of Computer Research & Technology, National Institutes of Health, Bethesda, Maryland 20892

  3. 3

    Pharmaceutics Department, Amgen, Inc., Thousand Oaks, California 91320

*Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139. Telephone: 617-258-5021; Fax: 617-258-5042

Publication History

  1. Issue published online: 27 OCT 2004
  2. Article first published online: 27 OCT 2004
  3. Manuscript Revised: 2 AUG 2004
  4. Manuscript Accepted: 2 AUG 2004
  5. Manuscript Received: 20 MAY 2004

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Keywords:

  • protein oxidation;
  • peroxides;
  • methionine;
  • molecular dynamics;
  • ab initio calculations;
  • GCSF;
  • hPTH(1-34)

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

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