Design, synthesis, and functionalization of dimeric peptides targeting chemokine receptor CXCR4.
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Design, synthesis, and functionalization of dimeric peptides targeting chemokine receptor CXCR4. / Demmer, Oliver; Dijkgraaf, Ingrid; Schumacher, Udo; Marinelli, Luciana; Cosconati, Sandro; Gourni, Eleni; Wester, Hans-Jürgen; Kessler, Horst.
in: J MED CHEM, Jahrgang 54, Nr. 21, 21, 2011, S. 7648-7662.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Design, synthesis, and functionalization of dimeric peptides targeting chemokine receptor CXCR4.
AU - Demmer, Oliver
AU - Dijkgraaf, Ingrid
AU - Schumacher, Udo
AU - Marinelli, Luciana
AU - Cosconati, Sandro
AU - Gourni, Eleni
AU - Wester, Hans-Jürgen
AU - Kessler, Horst
PY - 2011
Y1 - 2011
N2 - 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.
AB - 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.
KW - Animals
KW - Mice
KW - Ligands
KW - Binding Sites
KW - Models, Molecular
KW - Tissue Distribution
KW - Protein Binding
KW - Dimerization
KW - Positron-Emission Tomography
KW - Mice, Nude
KW - Receptors, CXCR4/metabolism
KW - Chelating Agents/chemical synthesis/chemistry
KW - Coordination Complexes/chemical synthesis/chemistry/pharmacokinetics
KW - Drug Design
KW - Gadolinium
KW - Heterocyclic Compounds, 1-Ring/chemistry
KW - Oligopeptides/chemical synthesis/chemistry/pharmacokinetics
KW - Peptides, Cyclic/chemical synthesis/chemistry/pharmacokinetics
KW - Radiopharmaceuticals/chemical synthesis/chemistry/pharmacokinetics
KW - Structure-Activity Relationship
KW - Animals
KW - Mice
KW - Ligands
KW - Binding Sites
KW - Models, Molecular
KW - Tissue Distribution
KW - Protein Binding
KW - Dimerization
KW - Positron-Emission Tomography
KW - Mice, Nude
KW - Receptors, CXCR4/metabolism
KW - Chelating Agents/chemical synthesis/chemistry
KW - Coordination Complexes/chemical synthesis/chemistry/pharmacokinetics
KW - Drug Design
KW - Gadolinium
KW - Heterocyclic Compounds, 1-Ring/chemistry
KW - Oligopeptides/chemical synthesis/chemistry/pharmacokinetics
KW - Peptides, Cyclic/chemical synthesis/chemistry/pharmacokinetics
KW - Radiopharmaceuticals/chemical synthesis/chemistry/pharmacokinetics
KW - Structure-Activity Relationship
M3 - SCORING: Journal article
VL - 54
SP - 7648
EP - 7662
JO - J MED CHEM
JF - J MED CHEM
SN - 0022-2623
IS - 21
M1 - 21
ER -