Complexation of an Antimicrobial Peptide by Large‐Sized Macrocycles for Decreasing Hemolysis and Improving Stability

Abstract Traditional macrocyclic hosts have finite cavity sizes, generally 5–10 Å, which are commonly adaptive to recognize small guests rather than biological macromolecules. Here two water‐soluble large‐sized quaterphen[ n ]arenes (WQPns, n =3, 4) were designed and synthesized. These two hosts present significantly distinct recognition abilities. Specifically, they could strongly complex an antimicrobial peptide, pexiganan (PXG) with the association constants ( K a ) of (4.20±0.23)×10 4 M −1 for PXG/WQP3 and (2.46±0.44)×10 5 M −1 for PXG/WQP4. Complexation of PXG by WQP3 and WQP4 served to decrease the hemolysis of PXG in rabbit red blood cells in a statistically significant way. Furthermore, host–guest complexation was shown to substantially enhance metabolic stability of PXG in presence of proteinase K, rat plasma and liver or kidney homogenates.