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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, Vol. 54, No. 21, 21, 2011, p. 7648-7662.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Demmer, O, Dijkgraaf, I, Schumacher, U, Marinelli, L, Cosconati, S, Gourni, E, Wester, H-J & Kessler, H 2011, 'Design, synthesis, and functionalization of dimeric peptides targeting chemokine receptor CXCR4.', J MED CHEM, vol. 54, no. 21, 21, pp. 7648-7662. <http://www.ncbi.nlm.nih.gov/pubmed/21905730?dopt=Citation>

APA

Demmer, O., Dijkgraaf, I., Schumacher, U., Marinelli, L., Cosconati, S., Gourni, E., Wester, H-J., & Kessler, H. (2011). Design, synthesis, and functionalization of dimeric peptides targeting chemokine receptor CXCR4. J MED CHEM, 54(21), 7648-7662. [21]. http://www.ncbi.nlm.nih.gov/pubmed/21905730?dopt=Citation

Vancouver

Demmer O, Dijkgraaf I, Schumacher U, Marinelli L, Cosconati S, Gourni E et al. Design, synthesis, and functionalization of dimeric peptides targeting chemokine receptor CXCR4. J MED CHEM. 2011;54(21):7648-7662. 21.

Bibtex

@article{606019580d2645258d737162f40eb3bf,
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.",
keywords = "Animals, Mice, Ligands, Binding Sites, Models, Molecular, Tissue Distribution, Protein Binding, Dimerization, Positron-Emission Tomography, Mice, Nude, Receptors, CXCR4/*metabolism, Chelating Agents/*chemical synthesis/chemistry, Coordination Complexes/*chemical synthesis/chemistry/pharmacokinetics, Drug Design, Gadolinium, Heterocyclic Compounds, 1-Ring/chemistry, Oligopeptides/*chemical synthesis/chemistry/pharmacokinetics, Peptides, Cyclic/*chemical synthesis/chemistry/pharmacokinetics, Radiopharmaceuticals/*chemical synthesis/chemistry/pharmacokinetics, Structure-Activity Relationship, Animals, Mice, Ligands, Binding Sites, Models, Molecular, Tissue Distribution, Protein Binding, Dimerization, Positron-Emission Tomography, Mice, Nude, Receptors, CXCR4/*metabolism, Chelating Agents/*chemical synthesis/chemistry, Coordination Complexes/*chemical synthesis/chemistry/pharmacokinetics, Drug Design, Gadolinium, Heterocyclic Compounds, 1-Ring/chemistry, Oligopeptides/*chemical synthesis/chemistry/pharmacokinetics, Peptides, Cyclic/*chemical synthesis/chemistry/pharmacokinetics, Radiopharmaceuticals/*chemical synthesis/chemistry/pharmacokinetics, Structure-Activity Relationship",
author = "Oliver Demmer and Ingrid Dijkgraaf and Udo Schumacher and Luciana Marinelli and Sandro Cosconati and Eleni Gourni and Hans-J{\"u}rgen Wester and Horst Kessler",
year = "2011",
language = "English",
volume = "54",
pages = "7648--7662",
journal = "J MED CHEM",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "21",

}

RIS

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 -