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

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 signifi...

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Published in:Angewandte Chemie International Edition 2021-05, Vol.60 (20), p.11288-11293
Main Authors: Chen, Junyi, Meng, Qingbin, Zhang, Yadan, Dong, Ming, Zhao, Liang, Zhang, Yahan, Chen, Longming, Chai, Yao, Meng, Zhao, Wang, Chenhong, Jia, Xueshun, Li, Chunju
Format: Article
Language:English
Subjects:
Antiinfectives and antibacterials
Antimicrobial agents
Antimicrobial peptides
Aromatic compounds
Complexation
Endopeptidase K
Erythrocytes
Hemolysis
host–guest complexation
Kidneys
large-sized macrocycles
Macromolecules
metabolic stability
Peptides
Proteinase
Stability
Statistical analysis
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Summary: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 (Ka) of (4.20±0.23)×104 M−1 for PXG/WQP3 and (2.46±0.44)×105 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. Two water‐soluble large‐sized quaterphen[n]arenes (WQPns, n=3, 4) were designed and synthesized. Macrocycles WQP3 and WQP4 could strongly complex with an antimicrobial peptide, pexiganan (PXG). Host–guest complexation served to not only efficiently decrease the PXG's hemolysis in rabbit red blood cells, but also substantially enhance its metabolic stability in presence of proteinase K, rat plasma and liver or kidney homogenates.
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.202102706