Discovery of an evolutionarily distinct evasin with dual CC and CXC chemokine inhibitory activity

Chemokine-driven leukocyte trafficking is central to the pathogenesis of cancer and autoimmune/inflammatory diseases. Therapeutic targeting of the chemokine system has largely failed due to promiscuous binding between chemokines and their receptors. Blood-feeding ticks evade immune responses by secreting salivary evasins that selectively bind and neutralize either CC or CXC chemokines. Here, we describe EVA-ATL1001 (EVA-ATL), an evasin with dual CC/CXC inhibitory function. Like other class A evasins, EVA-ATL engages CC chemokines through conserved hydrogen bonds between its β1 region and the chemokine CC motif. Remarkably, the same interface accommodates CXC chemokines with minor structural adjustments. This dual recognition is mediated primarily by a shallow hydrophobic pocket, along with contributions from the N-terminus and β1-β2 region, features absent in other evasins. EVA-ATL represents a natural evasin with broad-spectrum CC/CXC chemokine inhibition, offering a promising framework for next-generation immunotherapeutics for complex pathologies involving both chemokine families.