Peptidomimetic Pillar[5]arene Derivatives Bearing Aromatic α-Amino Acid Fragments as Supramolecular Shields: Preventing Adverse Cyclosporine A-Calcium Ion Interactions.

The application of supramolecular chemistry approaches involving multivalent macrocyclic derivatives offers a potential strategy to prevent adverse drug-macroelement interactions under conditions of electrolyte abnormalities. In this work, a peptidomimetic concept was employed to synthesize water-soluble, nontoxic pillar[5]arene derivatives bearing L-phenylalanine fragments. The macrocycles demonstrated affinity for the known immunosuppressant Cyclosporine A (CsA), resulting in the formation of assemblies with varying size and morphology, as evidenced by dynamic light scattering and transmission electron microscopy. UV-vis, fluorescence, and circular dichroism spectroscopies were employed for both the qualitative and quantitative assessment of the interaction between the pillar[5]arenes and CsA (lg Ka values for the two systems were determined to be 5.16 and 5.03), and to confirm that conformational changes in the CsA structure were prevented upon association. Molecular docking predicted the binding mode of the synthesized pillar[5]arenes with CsA, indicating the likely formation of rotaxane-type structures, which remained stable over a 70-100 ns simulation range. Furthermore, the water-soluble macrocycle in a binary pillar[5]arene+CsA system demonstrated a protective function, suppressing the undesirable interaction of the immunosuppressant with calcium ions, despite the drug's high intrinsic affinity for this macroelement. The results highlight the promise of these peptidomimetic macrocycles as supramolecular shields for mitigating uncontrolled drug-ion interactions in disrupted homeostasis.