title: Targeting SDF-1/CXCL12 with a ligand that prevents activation of CXCR4 through structure-based drug design.
abstract: CXCL12 is an attractive target for clinical therapy because of its involvement in autoimmune diseases, cancer growth, metastasis, and neovascularization. Tyrosine sulfation at three positions in the CXCR4 N-terminus is crucial for specific, high-affinity CXCL12 binding. An NMR structure of the complex between the CXCL12 dimer and a sulfotyrosine-containing CXCR4 fragment enabled high-throughput in silico screening for inhibitors of the chemokine-receptor interface. A total of 1.4 million compounds from the ZINC database were docked into a cleft on the CXCL12 surface normally occupied by sulfotyrosine 21 (sY21), and five were selected for experimental screening. NMR titrations with CXCL12 revealed that four of the compounds occupy the sY21 site, one of which binds with a K(d) of 64 microM. This compound selectively inhibits SDF1-induced CXCR4 signaling in THP1 cells. Our results suggest that sulfotyrosine recognition sites can be targeted for the development of novel chemokine inhibitors.
authors.affiliation: Department of Biochemistry, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, Wisconsin 53226, USA.
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Veldkamp
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Ziarek
authors.forename: Francis C
authors.initials: FC
authors.lastname: Peterson
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.forename: Brian F
authors.initials: BF
authors.lastname: Volkman
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D054377:Chemokine CXCL12 / Q000037:antagonists & inhibitors*; D003198:Computer Simulation; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008024:Ligands; D008956:Models, Chemical; D019718:Receptors, CXCR4 / Q000819:agonists / Q000037:antagonists & inhibitors*; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D054377:Chemokine CXCL12; D008024:Ligands; D019718:Receptors, CXCR4; D054852:Small Molecule Libraries
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