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Open AccessArticle

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

1
Center for Targeted Drug Delivery, Department of Biomedical and Pharmaceutical Sciences, Harry and Diane Rinker Health Science Campus, Chapman University School of Pharmacy, Irvine, CA 92618, USA
2
Department of Chemistry, Deenbandhu Chhotu Ram University of Science and Technology, Murthal, Haryana 131039, India
3
School of Biotechnology, KIIT Deemed to be University, Bhubaneswar 751024, India
4
Peptide Chemistry Department, National Research Centre, Dokki, Cairo 12622, Egypt
*
Authors to whom correspondence should be addressed.
Pharmaceutics 2020, 12(9), 842; https://doi.org/10.3390/pharmaceutics12090842
Received: 8 August 2020 / Revised: 29 August 2020 / Accepted: 31 August 2020 / Published: 3 September 2020
(This article belongs to the Special Issue Peptide-Based Drug Delivery Systems)
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. View Full-Text
Keywords: antibacterial activity; cell-penetrating peptide; cyclic peptide; tricyclic; cellular uptake; cytotoxicity; drug delivery; MDA-MB-231; phosphopeptide; siRNA antibacterial activity; cell-penetrating peptide; cyclic peptide; tricyclic; cellular uptake; cytotoxicity; drug delivery; MDA-MB-231; phosphopeptide; siRNA
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MDPI and ACS Style

Kumar, S.; Mandal, D.; El-Mowafi, S.A.; Mozaffari, S.; Tiwari, R.K.; Parang, K. Click-Free Synthesis of a Multivalent Tricyclic Peptide as a Molecular Transporter. Pharmaceutics 2020, 12, 842.

AMA Style

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.

Chicago/Turabian Style

Kumar, Sumit; Mandal, Dindyal; El-Mowafi, Shaima A.; Mozaffari, Saghar; Tiwari, Rakesh K.; Parang, Keykavous. 2020. "Click-Free Synthesis of a Multivalent Tricyclic Peptide as a Molecular Transporter" Pharmaceutics 12, no. 9: 842.

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