Development of mimokines, a new class of short CXCR4 antagonists mimicking natural chemokines


CALL: 2009

DOMAIN: BM - Translational Biomedical Research


LAST NAME: Chevigne




KEYWORDS: CXCR4, chemokines, cancer, phage display technology, mimokines and peptides

START: 2010-01-01

END: 2011-12-31


Submitted Abstract

The chemokine receptor CXCR4 expressed on a variety of cells interacts with a uniqueCXC chemokine ligand 12 (CXCL12) and regulates B cell lymphopoiesis, hematopoietic stemcell and leucocyte mobilization. In addition to its important role in inflammation, the chemokinereceptor CXCR4 acts also as the coreceptor for T-cell tropic Human Immunodeficiency Virustype 1 (HIV-1), one of the causative agents of AIDS. Furthermore, a prominent role of CXCR4was described in cancer and tumour biology. The interaction of CXCR4 with CXCL12 promotes:(1) cell motility and invasion of cancer cells leading to metastasis and (2) cancer cell survivaland proliferation. Although more than 90% of the cancer related deaths are due to metastaticprocesses, no approved drugs targeting metastasis development are yet available. Therefore,the development of new molecules targeting the interactions between CXCR4 and CXCL12 isof great importance to tackle both cancer and HIV.The objectives of the current proposal are (1) engineering of new phage libraries displayingrandomized short N-terminal chemokine fragments called “mimokines”, (2) screening of themimokine phage libraries on a simplified CXCR4 model, cells expressing CXCR4 and purifiedCXCR4 receptor to isolate strong CXCR4 binding mimokines and (3) validation of the bindingand the specificity of the isolated mimokines to integral CXCR4.An absolute prerequisite for the development of receptor antagonists is the receptorselectivity of the antagonist. Intrinsic drawbacks associated to natural chemokines are their lackof selectivity in chemokine-receptor interactions. This phenomenon leads to unwanted sideeffects when these complete chemokines are used as therapeutic molecules. Therefore, wepropose in this project to minimize the size of the chemokines to a peptide level with anenhanced selectivity. The chemokines will be down-sized to peptides corresponding to the Nterminusof the chemokines and controlled in vitro randomizations will be introduced to createphage libraries of mutated chemokine fragments called “mimokines”.The isolation of mimokines specific to CXCR4 will be performed by developing screeningstrategies with phage libraries on a simplified CXCR4 model constituted of peptidescorresponding to the extracellular loops of the receptor. In parallel, the same libraries will bescreened on cells expressing the CXCR4 receptor and purified CXCR4 receptor. Bindingassays using flow cytometry and confocal microscopy with cells expressing CXCR4 and controlcells expressing irrelevant chemokine receptors will provide data on the CXCR4 specificity ofthe mimokines used as complete phage or as synthetic peptides.In summary, the outcome of this project will provide (1) phage displayed “mimokine”libraries of high complexity, (2) CXCR4 specific mimokines that will serve as lead compoundsfor future projects in which their therapeutic potential for cancer and HIV patients will be studiedand (3) the proof of principle for the mimokine strategy combined with the screening on asimplified CXCR4 receptor. This strategy could then be applied to other chemokines and theirreceptors involved in human pathologies to identify new therapeutic receptor ligands.

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