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We have engineered GPCR (G protein-coupled receptor) knock-out and high GAG-binding affinity into CXCL12α to inhibit CXCL12α-induced cell migration. Compared to wtCXCL12, the mutant CXCL12α (Δ8 L29K V39K) exhibited a 5.6-fold and a 2.2-fold affinity increase for heparin and heparan sulfate, respectively. From NaCl-based heparin displacement chromatography we concluded that more amino acid replacements would lead to altered GAG (glycosaminoglycan) ligand specificity. GAG silencing by this mutant was shown in a murine seeding model of human cancer cells, whereby a greatly reduced number of liver metastases was detected when the animals were treated intravenously with 1mg/kg CXCL12α (Δ8 L29K V39K) before cancer cell application.

Original publication

DOI

10.1016/j.febslet.2015.07.052

Type

Journal article

Journal

FEBS Lett

Publication Date

14/09/2015

Volume

589

Pages

2819 - 2824

Keywords

Cancer therapy, Carbohydrate binding protein, Chemokine, Glycosaminoglycan, Protein engineering, Tumour metastasis, Animals, Cell Line, Tumor, Chemokine CXCL12, Female, Gene Silencing, Glycosaminoglycans, Humans, Liver, Mice, Mutation, Protein Engineering, Receptors, G-Protein-Coupled, Signal Transduction