Inhibition of the Pro-Malignancy Chemokine CCL5 by "40s Loop Mimetics"

The inflammatory microenvironment of tumors, comprised of cells, chemokines and cytokines, was recently shown to have a major role in cancer development and progression. The inflammatory chemokine CCL5 is secreted by tumor cells or by other cells in the tumor milieu and acts as a tumor-promoting factor in many malignancies. Its pro-cancerous activities are mediated by the binding of CCL5 to glycosaminoglycans (GAGs) and to CCL5 receptors, mainly through positively-charged amino acid sequence of 44-RKNR-47 located at the 40s loop of the chemokine. Our overall goal in this study is to develop new therapeutic modalities that would prevent cancerous processes that are based on CCL5 activities.

To this end, we have designed a CCL5-loop mimetic, called herein RKNR-CCL5-peptide. This peptide is a unique inhibitory technique of CCL5-driven inflammatory conditions which is based on the artificial looping of the 40s domain of CCL5. Preliminary analyses that we have performed indicate that the RKNR-CCL5-peptide inhibits the binding of WT CCL5 to GAGs and the migration of monocytic cells in response to GAG-presented WT CCL5 in vitro.

Overall, our results provide initial support to the ability of the RKNR-CCL5-pepide to inhibit activities induced by full-length WT CCL5. These findings may have clinical relevance in all malignancies in which CCL5 is involved. Therefore, a better identification of the RKNR-CCL5-peptide inhibitory effects is necessary and may set the basis for the future design of innovative strategy to treat malignant diseases.