Publications by authors named "Samara Hanna"

2 Publications

  • Page 1 of 1

Cyclic Peptides as Protein Kinase Inhibitors: Structure-Activity Relationship and Molecular Modeling.

J Chem Inf Model 2021 06 17;61(6):3015-3026. Epub 2021 May 17.

Center for Targeted Drug Delivery, Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Harry and Diane Rinker Health Science Campus, Irvine, California 92618, United States.

Under-expression or overexpression of protein kinases has been shown to be associated with unregulated cell signal transduction in cancer cells. Therefore, there is major interest in designing protein kinase inhibitors as anticancer agents. We have previously reported [WR], a peptide containing alternative arginine (R) and tryptophan (W) residues as a non-competitive c-Src tyrosine kinase inhibitor. A number of larger cyclic peptides containing alternative hydrophobic and positively charged residues [WR] ( = 6-9) and hybrid cyclic-linear peptides, [RK]W and [RK]W, containing R and W residues were evaluated for their protein kinase inhibitory potency. Among all the peptides, cyclic peptide [WR] was found to be the most potent tyrosine kinase inhibitor. [WR] showed higher inhibitory activity (IC = 0.21 μM) than [WR], [WR], [WR], and [WR] with IC values of 0.81, 0.57, 0.35, and 0.33 μM, respectively, against c-Src kinase as determined by a radioactive assay using [γ-P]ATP. Consistent with the result above, [WR] inhibited other protein kinases such as Abl kinase activity with an IC value of 0.35 μM, showing 2.2-fold higher inhibition than [WR] (IC = 0.79 μM). [WR] also inhibited PKCa kinase activity with an IC value of 2.86 μM, approximately threefold higher inhibition than [WR] (IC = 8.52 μM). A similar pattern was observed against Braf, c-Src, Cdk2/cyclin A1, and Lck. [WR] exhibited IC values of <0.25 μM against Akt1, Alk, and Btk. These data suggest that [WR] is consistently more potent than other cyclic peptides with a smaller ring size and hybrid cyclic-linear peptides [RK]W and [RK]W against selected protein kinases. Thus, the presence of R and W residues in the ring, ring size, and the number of amino acids in the structure of the cyclic peptide were found to be critical in protein kinase inhibitory potency. We identified three putative binding pockets through automated blind docking of cyclic peptides [WR]. The most populated pocket is located between the SH2, SH3, and N-lobe domains on the opposite side of the ATP binding site. The second putative pocket is formed by the same domains and located on the ATP binding site side of the protein. Finally, a third pocket was identified between the SH2 and SH3 domains. These results are consistent with the non-competitive nature of the inhibition displayed by these molecules. Molecular dynamics simulations of the protein-peptide complexes indicate that the presence of either [WR] or [WR] affects the plasticity of the protein and in particular the volume of the ATP binding site pocket in different ways. These results suggest that the second pocket is most likely the site where these peptides bind and offer a plausible rationale for the increased affinity of [WR].
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http://dx.doi.org/10.1021/acs.jcim.1c00320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238896PMC
June 2021

Comparative Molecular Transporter Efficiency of Cyclic Peptides Containing Tryptophan and Arginine Residues.

ACS Omega 2018 Nov 29;3(11):16281-16291. Epub 2018 Nov 29.

Center for Targeted Drug Delivery, Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Harry and Diane Rinker Health Science Campus, Irvine, California 92618, United States.

Cyclic peptides containing tryptophan (W) and arginine (R) residues, [WR], [WR], [WR], [WR], and [WR], were synthesized through Fmoc solid-phase chemistry to compare their molecular transporter efficiency. The in vitro cytotoxicity of the peptides was evaluated using human leukemia carcinoma cell line (CCRF-CEM) and normal kidney cell line (LLC-PK1). [WR], [WR], [WR], and [WR] were not significantly cytotoxic to LLC-PK1cells at a concentration of 10 μM after 3 h incubation. Among all the peptides, [WR] was found to be a more efficient transporter than [WR], [WR], [WR], and [WR] in CCRF-CEM cells for delivery of a cell-impermeable fluorescence-labeled negatively charged phosphopeptide (F'-GpYEEI). [WR] (10 μM) improved the cellular uptake of F'-GpYEEI (2 μM) by 20-fold. The cellular uptake of a fluorescent conjugate of [WR], F'-[WRK], was increased in a concentration- and time-dependent pattern in CCRF-CEM cells. The uptake of F'-[WRK] was slightly reduced in CCRF-CEM cells in the presence of different endocytic inhibitors, such as nystatin, 5-(-ethyl--isopropyl)amiloride, chlorpromazine, chloroquine, and methyl β-cyclodextrin. Furthermore, the uptake of F'-[WRK] was shown to be temperature-dependent and slightly adenosine 5'-triphosphate-dependent. The intracellular/cellular localization (in the nucleus and cytoplasm) of F'-[WRK] was confirmed by fluorescent microscopy in CCRF-CEM cells. These studies suggest that large cyclic peptides containing arginine and tryptophan can be used as a molecular transporter of specific compounds.
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http://dx.doi.org/10.1021/acsomega.8b02589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6643651PMC
November 2018
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