Synthesis and biological evaluation of Bicyclic Peptides containing Arginine and Tryptophan residues

bicyclic peptide for drug delivery

Authors

  • Shaban Darwish National Research Centre, Egypt
  • Saghar Mozaffari Chapman University, CA, USA
  • Eman Mohammed Chapman University, CA, USA
  • Zahra Mahdieh Chapman University, CA, USA
  • Rakesh K. Tiwari Western University of Health Sciences, Lebanon, OR, USA
  • Keykavous Parang Chapman University, CA, USA

DOI:

https://doi.org/10.62110/sciencein.cbl.2024.v11.678

Keywords:

Antibacterial, Bicyclic peptides, Cell-penetrating peptides, Cellular uptake, Cytotoxicity, Phosphopeptides, Drug resistance, Drug Delivery

Abstract

Two bicyclic peptides, [W(WR)4K]-GFLG-[W(WR)8E] and [W(WR)4K]-[W(WR)4E], composed of alternate tryptophan (W) and arginine (R) residues in each monocyclic peptide building block connected through a lysine linker or a short cathepsin B tetrapeptide ligand, were synthesized. The minimum inhibitory concentration (MIC) values for a number of peptides were evaluated against different Gram-positive and Gram-negative bacterial strains. [W(WR)4K]-GFLG showed antibacterial activity against Gram-positive methicillin-resistant S. aureus (ATCC BAA-1556) and S. aureus (ATCC 29213) bacteria with MIC values of 16 µg/mL. The cytotoxicity of monocyclic peptide [W(WR)4K]-GFLG was evaluated against human liver (HepG2), kidney (HEK293), and lung (A549) cells after 24 h incubation, showing a CC50 > 300 µM. Furthermore, bicyclic peptides [W(WR)4K]-GFLG-[W(WR)8E] and [W(WR)4K]-[W(WR)4E] did not show any significant cytotoxicity at a concentration of 25 µM against human leukemia adenocarcinoma (CCRF-CEM) cells after 3 h incubation. These peptides were found to be effective molecular transporters for the delivery of a negatively charged phosphopeptide, enhancing the cellular delivery of a fluorescein (F´)-labeled phosphopeptide, F´-GpYEEI (F´-PP) (5 µM), by 6.5- and 4.5-fold, respectively, in CCRF-CEM cells after 3 h incubation when used at a concentration of 25 µM. These data suggest that these peptides can be used as cellular delivery tools.

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Author Biographies

  • Shaban Darwish, National Research Centre, Egypt

    Organometallic and Organometalloid Chemistry Department

  • Saghar Mozaffari, Chapman University, CA, USA

    Department of Biomedical and Pharmaceutical Sciences,
    Center for Targeted Drug Delivery, Chapman University School of Pharmacy,
    Harry and Diane Rinker Health Science Campus, Irvine, CA 92866, USA 

  • Eman Mohammed, Chapman University, CA, USA

    Department of Biomedical and Pharmaceutical Sciences,
    Center for Targeted Drug Delivery, Chapman University School of Pharmacy,
    Harry and Diane Rinker Health Science Campus, Irvine, CA 92866, USA 

  • Zahra Mahdieh, Chapman University, CA, USA

    Department of Biomedical and Pharmaceutical Sciences,
    Center for Targeted Drug Delivery, Chapman University School of Pharmacy,
    Harry and Diane Rinker Health Science Campus, Irvine, CA 92866, USA 

  • Rakesh K. Tiwari, Western University of Health Sciences, Lebanon, OR, USA

    Department of Basic Medical Sciences,
    College of Osteopathic Medicine of the Pacific-Northwest,

  • Keykavous Parang, Chapman University, CA, USA

    Department of Biomedical and Pharmaceutical Sciences,
    Center for Targeted Drug Delivery, Chapman University School of Pharmacy,
    Harry and Diane Rinker Health Science Campus, Irvine, CA 92866, USA

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Published

2024-08-12

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Articles

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How to Cite

(1)
Darwish, S. .; Mozaffari, S.; Mohammed, E.; Mahdieh, Z.; Tiwari, R. K.; Parang, K. Synthesis and Biological Evaluation of Bicyclic Peptides Containing Arginine and Tryptophan Residues. Chem Biol Lett 2024, 11 (4), 678. https://doi.org/10.62110/sciencein.cbl.2024.v11.678.

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