Disruption Of Chemokine Interactions Inhibits Atherosclerosis In Mice
Research published in Nature Medicine shows that the disruption of the interactions between two small signaling proteins called chemokines by a highly potent drug-like peptide inhibits the development of atherosclerosis in mice. San Diego-based Carolus Therapeutics Inc., which has in-licensed technology based on these and other findings of collaborators at RWTH Aachen University in Aachen, Germany, is focused on the discovery and development of drugs for the treatment of atherosclerosis and other disorders triggered by acute and chronic inflammation.
In their report, which was published online yesterday, RWTH Aachen University researchers demonstrated in a mouse model that the formation of heteromers of the chemokines platelet factor-4 (PF4, also known as CXCL4) and RANTES (CCL5) plays a regulatory role in the development of atherosclerosis. The scientists also showed that peptides designed to disrupt the formation of PF4-RANTES heteromers inhibited the development of atherosclerosis in mice that had a genetic propensity to develop the disease. (Koenen et al., Nature Med, 2009)
"Disrupting interactions between PF4 and RANTES is a novel approach to targeting inflammation that may lead to a new class of medications for the treatment of a variety of chronic and acute inflammatory diseases," said Jay Lichter, Ph.D., CEO of Carolus Therapeutics. "This approach could help to meet the unmet need for anti-inflammatory therapeutics for chronic diseases such as atherosclerosis, autoimmune diseases, rheumatoid arthritis, sepsis, asthma and multiple sclerosis."
PF4 and RANTES are chemokines that are secreted by platelets. Heteromerization of PF4 and RANTES results in recruitment of monocytes (a type of white blood cell and part of the body's immune system) to the arterial wall, causing the inflammation that is characteristic of atherosclerosis.
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."