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J. Biol. Chem., Vol. 276, Issue 36, 33465-33470, September 7, 2001

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Reengineering Granulocyte Colony-stimulating Factor for Enhanced Stability^*

Barney Bishop, Debbie C. Koay^§, Alan C. Sartorelli^§, and Lynne Regan^¶

From the Departments of  Chemistry and the ^¶ Molecular Biophysics and Biochemistry, Yale University and the ^§ Department of Pharmacology and Developmental Therapeutics Program, Cancer Center, Yale University School of Medicine, New Haven, Connecticut 06520

Granulocyte colony-stimulating factor is a long-chain cytokine that has both biological and therapeutic applications. It is involved in the production and maturation of neutrophilic progenitor cells and neutrophils and is administered to stimulate the production of white blood cells to reduce the risk of serious infection in immunocompromised patients. We have reengineered granulocyte colony-stimulating factor to improve the thermodynamic stability of the protein, focusing on enhancing the -helical propensity of residues in the antiparallel 4-helix bundle of the protein. These redesigns resulted in proteins with substantially enhanced stability while retaining wild-type levels of biological activity, measured as the ability of the reengineered proteins to stimulate the proliferation of murine myeloid cells transfected with the granulocyte colony-stimulating factor receptor.

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