Decoding an ancient parasite: Evasin-derived peptides capable of promiscuous chemokine binding as a new therapeutic approach to target cardiovascular inflammation

Chemokines are secreted signalling peptides that are central to immuno-inflammatory diseases. The theranostic (i.e. therapeutic and diagnostic) potential of targeting chemokines is unmet due to chemokine redundancy. Natural chemokine-binding proteins (CKBPs) from ticks and viruses bind multiple chemokines, blocking chemokine-receptor binding, and chemokine-dimerization, overcoming redundancy. CKBPs are effective in several disease models of inflammation, and as inflammation imaging agents.

A key question is how do CKBPs achieve their remarkable chemokine-binding properties combining high-affinity with multi-chemokine binding? A second question is how do CKBPs neutralize chemokine function? Understanding these mechanisms will instruct the development of peptide/peptidomimetic therapeutics and imaging agents. CKBP-chemokine interactions are mediated by short-linear-interacting-motifs (SLiMs), and certain CKBP-SLiMs bind multiple chemokines, inhibit chemokine function by steric hindrance of receptor binding, glycosaminoglycan (GAG) binding and dimerization, and are active in inflammation models in vivo. This suggests that CKBP-SLiM-peptides have potential for development as theranostic agents in immuno-inflammatory diseases.

In phase 1 of this project, we will identify CKBP-SLiMs using phage display and characterise CKBP-SLiM peptides using physico-chemical/biological approaches, including ex vivo inflammation models, to establish proof-of-concept.  In phase 2, we will chemically modify candidate CKBP-SLiM-peptides to develop theranostic agents for study in animal models of cardiovascular immuno-inflammation.

Image title: Phage display schematic