title: Design, synthesis, and functionalization of dimeric peptides targeting chemokine receptor CXCR4.
abstract: The chemokine receptor CXCR4 is a critical regulator of inflammation and immune surveillance, and it is specifically implicated in cancer metastasis and HIV-1 infection. On the basis of the observation that several of the known antagonists remarkably share a C(2) symmetry element, we constructed symmetric dimers with excellent antagonistic activity using a derivative of a cyclic pentapeptide as monomer. To optimize the binding affinity, we investigated the influence of the distance between the monomers and the pharmacophoric sites in the synthesized constructs. The affinity studies in combination with docking computations support a two-site binding model. In a final step, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) was introduced as chelator for (radio-)metals, thus allowing to exploit these compounds as a new group of CXCR4-binding peptidic probes for molecular imaging and endoradiotherapeutic purposes. Both the DOTA conjugates and some of their corresponding metal complexes retain good CXCR4 affinity, and one (68)Ga labeled compound was studied as PET tracer.
authors: Institute for Advanced Study, Technische Universität München , Lichtenbergstrasse 4, D-85748 Garching, Germany.
authors: Oliver
authors: O
authors: Demmer
authors: Ingrid
authors: I
authors: Dijkgraaf
authors: Udo
authors: U
authors: Schumacher
authors: Luciana
authors: L
authors: Marinelli
authors: Sandro
authors: S
authors: Cosconati
authors: Eleni
authors: E
authors: Gourni
authors: Hans-Jürgen
authors: HJ
authors: Wester
authors: Horst
authors: H
authors: Kessler
mesh_terms: D000818:Animals; D001665:Binding Sites; D002614:Chelating Agents / Q000138:chemical synthesis* / Q000737:chemistry; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D019281:Dimerization; D015195:Drug Design; D005682:Gadolinium; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry; D008024:Ligands; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography; D011485:Protein Binding; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D019718:Receptors, CXCR4 / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D002614:Chelating Agents; D056831:Coordination Complexes; D006573:Heterocyclic Compounds, 1-Ring; D008024:Ligands; D009842:Oligopeptides; D010456:Peptides, Cyclic; D019275:Radiopharmaceuticals; D019718:Receptors, CXCR4; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D005682:Gadolinium