The complex inter-relationships between protein flexibility and stability

Authors

  • Tim J. Kamerzell,

    Corresponding author
    1. Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, Kansas 66047
    Current affiliation:
    1. Department of Late Stage Pharmaceutical and Device Development, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080.
    • Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, Kansas 66047. Telephone: 650-225-6630; Fax: 650-225-3613.
    Search for more papers by this author
  • C. Russell Middaugh

    1. Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, Kansas 66047
    Search for more papers by this author

Abstract

The ability to successfully formulate and manufacture therapeutic protein dosage forms requires a thorough understanding of their physico-chemical properties. Proteins are inherently dynamic molecules of marginal stability. These properties present unique challenges to the pharmaceutical scientist attempting to develop protein based therapeutics. The physicochemical stability and biological functions of proteins are thought to be intimately related to their global flexibility, intramolecular fluctuations and various other dynamic processes. Our understanding of these relationships, however, is incomplete but undeniably necessary for the development of efficacious therapies. Therefore, a better understanding of the complex inter-relationships between protein flexibility and stability should enable the rational design and optimization of protein formulation conditions based on protein dynamics. This review attempts to define protein dynamics and flexibility while summarizing a select number of studies of potential pharmaceutical interest that evaluate these relationships. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:3494–3517, 2008

Ancillary