Rigid Macrocycle Metal Complexes as CXCR4 Chemokine Receptor Antagonists: Influence of Ring Size.

Understanding the role of chemokine receptors in health and disease has been of increasing interest in recent years. Chemokine receptor CXCR4 has been extensively studied because of its defined role in immune cell trafficking, HIV infection, inflammatory diseases, and cancer progression. We have developed high affinity rigidified CXCR4 antagonists that incorporate metal ions to optimize the binding interactions with the aspartate side chains at the extracellular surface of the CXCR4 chemokine receptor and increase the residence time.

Binding optimization through coordination chemistry: CXCR4 chemokine receptor antagonists from ultrarigid metal complexes.

A new copper(II) containing bis-macrocyclic CXCR4 chemokine receptor antagonist is shown to have improved binding properties to the receptor protein in comparison to the drug AMD3100 (Plerixafor, Mozobil). The interaction of the metallodrug has been optimized by using ultrarigid chelator units that offer an equatorial site for coordination to the amino acid side chains of the protein. Binding competition assays with anti-CXCR4 antibodies show that the new compound stays bound longer and it has improved anti-HIV potency in vitro (EC(50) = 4.