This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The cell-surface CXCR4 chemokine receptor is over-expressed in human malignant and metastatic breast cells but is not present in normal breast tissue. This receptor is involved in the metastasis of breast and other types of tumor cells. Hence, we hypothesize that blocking this receptor with synthetic peptide ligands offers the potential for a new class of chemotherapeutic agents targeted specifically to prevent cancer metastasis. In order to test this hypothesis our first step was to design, synthesize and evaluate synthetic peptide ligands as potential CXCR4 receptor antagonists. Using a radioligand binding assay, our results demonstrate that several of our analogues have high affinity for CXCR4. Further, these ligands are antagonists as they are able to successfully reverse agonist activity of the endogenous ligand at CXCR4 in a GTPase functional assay. However, our most exciting finding stems from the inability to correlate receptor affinity with antagonist potency for our series of analogues. The 150-fold increase in antagonist potency of our new lead compound could not have been predicted from receptor affinity that suggests the potential for a new paradigm for peptide ligand interaction with CXCR4. Our future work focuses on the central hypothesis that structural requirements for peptide-based antagonists are not identical to those of the endogenous protein for interaction at CXCR4. We will further investigate the interaction between peptides and CXCR4 using a two-tiered method. This will include chemical modification of the peptides in combination with molecular biology approaches to modify the receptor.
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