Click-Free Synthesis of a Multivalent Tricyclic Peptide as a Molecular Transporter

Authors

Sumit Kumar, Chapman UniversityFollow
Dindyal Mandal, Chapman UniversityFollow
Shaima Ahmed El-Mowafi, Chapman UniversityFollow
Saghar Mozaffari, Chapman UniversityFollow
Rakesh Kumar Tiwari, Chapman UniversityFollow
Keykavous Parang, Chapman UniversityFollow

Document Type

Article

Publication Date

9-3-2020

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.

Comments

This article was originally published in Pharmaceutics in 2020. https://doi.org/10.3390/pharmaceutics12090842

Recommended Citation

Kumar S, Mandal D, El-Mowafi SA, Mozaffari S, Tiwari RK, Parang K. Click-free synthesis of a multivalent tricyclic peptide as a molecular transporter. Pharmaceutics. 2020; 12(9):842. https://doi.org/10.3390/pharmaceutics12090842

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This work is licensed under a Creative Commons Attribution 4.0 License.