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Click-Free Synthesis of a Multivalent Tricyclic Peptide as a Molecular Transporter
- Source :
- Pharmaceutics, Vol 12, Iss 9, p 842 (2020)
- Publication Year :
- 2020
- Publisher :
- MDPI AG, 2020.
-
Abstract
- The cellular delivery of cell-impermeable and water-insoluble molecules remains an ongoing challenge to overcome. Previously, we reported amphipathic cyclic peptides c[WR]4 and c[WR]5 consisting of alternate arginine and tryptophan residues as nuclear-targeting molecular transporters. These peptides contain an optimal balance of positive charge and hydrophobicity, which is required for interactions with the phospholipid bilayer to facilitate their application as a drug delivery system. To further optimize them, we synthesized and evaluated a multivalent tricyclic peptide as an efficient molecular transporter. The monomeric cyclic peptide building blocks were synthesized using Fmoc/tBu solid-phase chemistry and cyclization in the solution and conjugated with each other through an amide bond to afford the tricyclic peptide, which demonstrated modest antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA), Klebsiella pneumoniae, Pseudomonas aeruginosa, and Escherichia coli (E. coli) with a minimum inhibitory concentration (MIC) of 64–128 µg/mL. The tricyclic peptide was found to be nontoxic up to 30 µM in the breast cancer cell lines (MDA-MB-231). The presence of tricyclic peptide enhanced cellular uptakes of fluorescently-labeled phosphopeptide (F’-GpYEEI, 18-fold), anti-HIV drugs (lamivudine (F’-3TC), emtricitabine (F’-FTC), and stavudine (F’-d4T), 1.7–12-fold), and siRNA (3.3-fold) in the MDA-MB-231 cell lines.
Details
- Language :
- English
- ISSN :
- 19994923
- Volume :
- 12
- Issue :
- 9
- Database :
- Directory of Open Access Journals
- Journal :
- Pharmaceutics
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.52c061eb0afa408883d27e1e0a03dc12
- Document Type :
- article
- Full Text :
- https://doi.org/10.3390/pharmaceutics12090842