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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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Demmer O,Dijkgraaf I,Schumacher U,Marinelli L,Cosconati S,Gourni E,Wester HJ,Kessler H

doi

10.1021/jm2009716

subject

Has Abstract

pub_date

2011-11-10 00:00:00

pages

7648-62

issue

21

eissn

0022-2623

issn

1520-4804

journal_volume

54

pub_type

杂志文章

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