Design, Synthesis, and Functionalization of Dimeric Peptides Targeting Chemokine Receptor CXCR4

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• 作者：Oliver Demmer ; Ingrid Dijkgraaf ; Udo Schumacher ; Luciana Marinelli ; Sandro Cosconati ; Eleni Gourni ; Hans-J眉rgen Wester ; Horst Kessler
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：November 10, 2011
• 年：2011
• 卷：54
• 期：21
• 页码：7648-7662
• 全文大小：1200K
• 年卷期：v.54,no.21(November 10, 2011)
• ISSN：1520-4804

文摘

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 C₂ 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 ⁶⁸Ga labeled compound was studied as PET tracer.