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P-Sulfonatocalix[4]Arene Turns Peptide Aggregates Into an Efficient Cell-Penetrating Peptide Publisher



Heydari M1 ; Salehi N2 ; Zadmard R3 ; Nau WM4 ; Khajeh K5 ; Azizi Z6 ; Norouzy A1
Authors
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Authors Affiliations
  1. 1. Bioprocess Engineering Department, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran
  2. 2. School of Biology, College of Science, University of Tehran, Tehran, Iran
  3. 3. Department of Organic Chemistry, Chemistry and Chemical Engineering Research Center of Iran, Tehran, Iran
  4. 4. School of Science, Constructor University, Bremen, Germany
  5. 5. Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
  6. 6. Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran

Source: RSC Advances Published:2024


Abstract

A novel cell-penetrating peptide (CPP) called FAM-Y4R4, with FAM as a fluorescent probe, was developed. Initially, we aimed to use Y4 as a supramolecular host for water-insoluble drugs, with R4 driving the complex into cells. However, an unexpected hurdle was discovered; the peptide self-assembled into amorphous aggregates, rendering it ineffective for our intended purpose. Molecular dynamics simulations revealed that intermolecular cation-π interactions between arginine and tyrosine caused this aggregation. By decorating the R4 sidechains with p-sulfonatocalix[4]arene (CX4), we successfully dissolved most of the aggregates, significantly improved the peptide's solubility and enhanced the cell uptake with MCF7 and A549 cells via both direct penetration and endocytosis. The binding strength between CX4 and R4, as well as the interaction between curcumin and tyrosines was quantified. Encouragingly, our results showed that FAM-Y4R4, with CX4, effectively delivered curcumin - as a model for poorly water-soluble drugs - into cells which exhibited potent anticancer activity. Using R4/CX4 instead of the conventional R7-9 oligoarginine-based CPP simplifies peptide synthesis and offers higher yields. CX4 shows promise for addressing aggregation issues in other peptides that undergo a similar aggregation mechanism. © 2024 The Royal Society of Chemistry.