Effect of backbone circularization on colloidal stability: Compaction of unfolded structures improves aggregation resistance of granulocyte colony-stimulating factor.

International Journal of Pharmaceutics
Risa ShibuyaShinya Honda

Abstract

Aggregation of protein therapeutics can lead to immunogenicity and loss of function in vivo. Its effective prevention requires an understanding of the conformational and colloidal stability of protein and the improvement of both. Granulocyte colony-stimulating factor (G-CSF), which is one of the most widely used protein therapeutics, was previously shown to be conformationally stabilized by connecting its N- and C-termini with amide bonds (backbone circularization). In this study, we investigated whether circularization affects the colloidal stability of proteins. Colloidal stability was indirectly assessed by analyzing the aggregation behavior of G-CSF variants using analytical ultracentrifugation (AUC) and small-angle X-ray scattering (SAXS). Consequently, we found that the unfolded structure of circularized G-CSF was more compact than non-circularized G-CSF, and that backbone circularization improved its aggregation resistance against chemical denaturation by guanidine hydrochloride (GdnHCl). The improved aggregation resistance suggests that the expansion tolerance of circularized G-CSF in the unfolded state increased its colloidal stability. Thus, backbone circularization is an excellent method for enhancing the colloidal a...Continue Reading

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