The RWTH Aachen University scientists characterized the structure of the PF4-RANTES interactions using NMR spectroscopy and then designed a series of peptides to disrupt those interactions. One such peptide, termed CKEY2, is comprised of sequences from the RANTES protein. CKEY2 was shown to be stable and formed the secondary structural motif found in RANTES when stabilized by disulfide bridged cysteines at both ends of the peptide. The scientists demonstrated that CKEY2 disrupts PF4-RANTES heteromer formation by binding preferentially to RANTES. In vitro assays demonstrated that CKEY2 inhibited the recruitment of monocytes to endothelial cells. Finally, the scientists demonstrated that mice that are genetically predisposed to develop atherosclerosis when fed a high fat diet did not develop chronic arterial inflammation when injected with the mouse version of the CKEY2 peptide.
"With the efficacy of the PF4-RANTES inhibitor established in preclinical studies for atherosclerosis, we are expanding our work into pre-clinical studies in other inflammatory disease models," said Josh Schultz, Ph.D., Carolus Therapeutics' vice president of research. "Our ongoing collaboration with RWTH Aachen University involves the further exploration of chemokine interactions involved in inflammatory signaling."
In addition to targeting PF4-RANTES heterodimers, Carolus Therapeutics has a second drug discovery program targeting the pro-inflammatory cytokine MIF (Macrophage Migration Inhibitory Factor), which has emerged as a critical mediator of innate, cell-mediated immunity, immunoregulation and inflammation. Carolus Therapeutics' scientific founders previously identified two CXC chemokine receptors as novel functional receptors for MIF. Identification of structural moti
|SOURCE Carolus Therapeutics Inc.|
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