title: Design, synthesis, and biological characterization of novel PEG-linked dimeric modulators for CXCR4.
abstract: CXCR4 dimerization has been widely demonstrated both biologically and structurally. This paper mainly focused on the development of structure-based dimeric ligands that target CXCL12-CXCR4 interaction and signaling. This study presents the design and synthesis of a series of [PEG]nlinked dimeric ligands of CXCR4 based on the knowledge of the homodimeric crystal structure of CXCR4 and our well established platform of chemistry and bioassays for CXCR4. These new ligands include [PEG]nlinked homodimeric or heterodimeric peptides consisting of either two DV3-derived moieties (where DV3 is an all-d-amino acid analog of N-terminal modules of 1-10 (V3) residues of vMIP-II) or hybrids of DV3 moieties and CXCL121-8. Among a total of 24 peptide ligands, four antagonists and three agonists showed good CXCR4 binding affinity, with IC50values of <50nM and <800nM, respectively. Chemotaxis and calcium mobilization assays with SUP-T1 cells further identified two promising lead modulators of CXCR4: ligand 4, a [PEG3]2linked homodimeric DV3, was an effective CXCR4 antagonist (IC50=22nM); and ligand 21, a [PEG3]2linked heterodimeric DV3-CXCL121-8, was an effective CXCR4 agonist (IC50=407nM). These dimeric CXCR4 modulators represent new molecular probes and therapeutics that effectively modulate CXCL12-CXCR4 interaction and function.
authors.affiliation: Department of Pharmacology, Upstate Medical University, State University of New York (SUNY), 750 Adams Street, Syracuse, NY 13210, USA; School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, China.
authors.forename: Yilei
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, Upstate Medical University, State University of New York (SUNY), 750 Adams Street, Syracuse, NY 13210, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Gao
authors.affiliation: Department of Pharmacology, Upstate Medical University, State University of New York (SUNY), 750 Adams Street, Syracuse, NY 13210, USA.
authors.forename: Qinghao
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, China; Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Chaozai
authors.initials: C
authors.lastname: Zhang
authors.affiliation: School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, China.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA. Electronic address: zhuang@ucsd.edu.
authors.forename: Ziwei
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Department of Pharmacology, Upstate Medical University, State University of New York (SUNY), 750 Adams Street, Syracuse, NY 13210, USA; Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA. Electronic address: jan@ucsd.edu.
authors.forename: Jing
authors.initials: J
authors.lastname: An
mesh_terms: D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D008024:Ligands; D011092:Polyethylene Glycols / Q000737:chemistry*; D019718:Receptors, CXCR4 / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C527276:CXCR4 protein, human; D008024:Ligands; D019718:Receptors, CXCR4; D011092:Polyethylene Glycols
keywords: CXCR4; Dimeric ligands; PEG