Chemokine N‐terminal‐derived peptides differentially regulate signaling by the receptors CCR1 and CCR5

Inflammatory chemokines are often elevated in disease settings, where the largest group of CC‐chemokines are the macrophage inflammatory proteins (MIP), which are promiscuous for the receptors CCR1 and CCR5. MIP chemokines, such as CCL3 and CCL5 are processed at the N terminus, which influences signaling in a highly diverse manner. Here, we investigate the signaling capacity of peptides corresponding to truncated N termini. These 3–10‐residue peptides displayed weak potency but, surprisingly, retained their signaling on CCR1. In contrast, none of the peptides generated a signal on CCR5, but a CCL3‐derived tetrapeptide was a positive modulator boosting the signal of several chemokine variants on CCR5. In conclusion, chemokine N termini can be mimicked to produce small CCR1‐selective agonists, as well as CCR5‐selective modulators.