Cytosolic Delivery of Bioactive Cyclic Peptide Cargo by Spontaneous Membrane Translocating Peptides.
| Autor: | Ferrie RP; Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, Louisiana 70112, United States., Fuselier T; Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, Louisiana 70112, United States., Wimley WC; Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, Louisiana 70112, United States. |
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| Jazyk: | angličtina |
| Zdroj: | ACS omega [ACS Omega] 2024 Feb 05; Vol. 9 (7), pp. 8179-8187. Date of Electronic Publication: 2024 Feb 05 (Print Publication: 2024). |
| DOI: | 10.1021/acsomega.3c08701 |
| Abstrakt: | Cyclic peptides that inhibit protein-protein interactions have significant advantages over linear peptides and small molecules for modulating cellular signaling networks in cancer and other diseases. However, the permeability barrier of the plasma membrane remains a formidable obstacle to the development of cyclic peptides into applicable drugs. Here, we test the ability of a family of synthetically evolved spontaneous membrane translocating peptides (SMTPs) to deliver phalloidin, a representative bioactive cyclic peptide, to the cytosol of human cells in culture. Phalloidin does not enter cells spontaneously, but if delivered to the cytosol, it inhibits actin depolymerization. We thus use a wound-healing cell mobility assay to assess the biological activity of phalloidin conjugated to three SMTPs that we previously discovered. All three SMTPs can deliver phalloidin to the cell cytosol, and one does so at concentrations as low as 3 μM. Delivery occurs despite the fact that the SMTPs were originally selected based on membrane translocation with no cargo other than a small fluorescent dye. These results show that SMTPs are viable delivery vehicles for cyclic peptides, although their efficiency is moderate. Further, these results suggest that one additional generation of synthetic molecular evolution could be used to optimize SMTPs for the efficient delivery of any bioactive cyclic peptide into cells. Competing Interests: The authors declare no competing financial interest. (© 2024 The Authors. Published by American Chemical Society.) |
| Databáze: | MEDLINE |
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