Design, synthesis, and functionalization of dimeric peptides targeting chemokine receptor CXCR4

J Med Chem. 2011 Nov 10;54(21):7648-62. doi: 10.1021/jm2009716. Epub 2011 Oct 11.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Chelating Agents / chemical synthesis*
  • Chelating Agents / chemistry
  • Coordination Complexes / chemical synthesis*
  • Coordination Complexes / chemistry
  • Coordination Complexes / pharmacokinetics
  • Dimerization
  • Drug Design
  • Gadolinium
  • Heterocyclic Compounds, 1-Ring / chemistry
  • Ligands
  • Mice
  • Mice, Nude
  • Models, Molecular
  • Oligopeptides / chemical synthesis*
  • Oligopeptides / chemistry
  • Oligopeptides / pharmacokinetics
  • Peptides, Cyclic / chemical synthesis*
  • Peptides, Cyclic / chemistry
  • Peptides, Cyclic / pharmacokinetics
  • Positron-Emission Tomography
  • Protein Binding
  • Radiopharmaceuticals / chemical synthesis*
  • Radiopharmaceuticals / chemistry
  • Radiopharmaceuticals / pharmacokinetics
  • Receptors, CXCR4 / metabolism*
  • Structure-Activity Relationship
  • Tissue Distribution


  • Chelating Agents
  • Coordination Complexes
  • Heterocyclic Compounds, 1-Ring
  • Ligands
  • Oligopeptides
  • Peptides, Cyclic
  • Radiopharmaceuticals
  • Receptors, CXCR4
  • 1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid
  • Gadolinium