Engineering Tick Evasins as Multitarget Chemokine Inhibitors─A Biomimetic Approach To Tackling the Complexity of the Immune System

ConspectusChemokines and their receptors are central regulators of leukocyte trafficking in both physiological immune surveillance and pathological inflammation. In chronic inflammatory diseases such as atherosclerosis, pulmonary fibrosis, rheumatoid arthritis, autoimmune disorders and cancer, dysregulated chemokine networks drive persistent and damaging immune cell infiltration. Given this central role, the chemokine system represents an attractive target for therapeutic intervention. However, despite decades of effort and substantial investment, most clinical trials targeting individual chemokines or chemokine receptors have failed to demonstrate clinical efficacy. A major limitation of the single-target approach lies in the redundancy and complexity of the chemokine network: multiple chemokines are often upregulated simultaneously in disease, each capable of activating overlapping but distinct receptor sets.Our laboratory's research focuses on discovering and engineering agents that can neutralize groups of functionally related chemokines, thereby blocking their collective pathological effects. Ticks, which must evade host immunity to feed for days, have evolved a powerful biological solution to target multiple chemokines. They secrete salivary proteins known as "evasins" that bind to and inhibit multiple chemokines. These small proteins offer a unique opportunity to engineer multichemokine inhibitors tailored to specific inflammatory profiles. In this Account, we describe our efforts to understand the molecular basis of evasin-chemokine recognition and to engineer these proteins into therapeutic scaffolds. Using bioinformatics, structural biology and mutagenesis, we have elucidated the atomic-level mechanisms underlying evasin selectivity, identified novel evasins with distinct chemokine-binding profiles, and developed structure-guided strategies to reprogram their selectivity. This Account also highlights complementary studies by other groups that have designed evasin-inspired peptides and employed <i>in vitro</i> evolution strategies to expand chemokine-binding selectivity.Together, these advances define the design principles governing multichemokine recognition and highlight how natural scaffolds can be repurposed for therapeutic applications. The engineering strategies discussed here also offer a generalizable roadmap for engineering or designing other proteins or peptides with multitarget "specificity".