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Engineering peptides for anticancer drug targeting and antimicrobial activity Open Access

Descriptions

Other title
Subject/Keyword
anticancer
antimicrobial peptides
drug targeting
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Soudy, Rania Nayel
Supervisor and department
Kaur, Kamaljit (Pharmacy and pharmaceutical sciences)
Examining committee member and department
Campell, Robert (chemistry)
Klotz, Lars-Oliver (Pharmacy and pharmaceutical sciences)
Velazquez, Carlos (Pharmacy and pharmaceutical sciences)
Uludag, Hasan (chemical engineering)
Kotra, Lakshmi ( Pharmacy, University of Toronto)
Department
Faculty of Pharmacy and Pharmaceutical Sciences
Specialization

Date accepted
2012-12-12T15:53:10Z
Graduation date
2013-06
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
Peptides hold great promise for clinical applications such as cancer and antimicrobial therapies. In cancer, conjugation of cancer treatments to tumor specific peptides improves their therapeutic efficiency. On the other side, antimicrobial peptides offer a great alternative for the conventional antibiotics against bacterial resistance and display selective anticancer activities with low toxicity. However, to obtain therapeutically applicable peptides, the chemical structures of lead sequences need to be further manipulated. The two main aims of this thesis were (i) to engineer cancer targeting peptides based on lead sequences NGR and p160 for enhanced proteolytic stability and binding affinity for cancer cells, (ii) engineer synthetic analogues of microcin J25 antimicrobial peptide, and improve its anticancer activity by augmenting its cellular uptake. First, a NGR peptide library was screened using peptide array-whole cell binding assay. This led to the identification several new peptides that targeted aminopeptidase N (CD13) receptor in the CD13+ cells. Specifically peptide 5 (YNGRT) displayed significant increase in CD13+ cells uptake compared to the lead peptide and displayed better APN enzyme inhibition. Second, p160 peptide analogues were engineered by replacement of two or three amino acids with D-residues or β3-amino acids for improved proteolytic stability while maintaining high specificity for breast cancer cells. Three analogues (18-4, 18-9, and 18-10) that exhibited resistance to proteolytic degradation in human serum and in liver homogenate and impart no cell cytotoxicity were identified. Further, two peptide-drug (Doxorubucin) conjugates were examined for their cancer drug targeting efficiency. Our results demonstrated that the ester conjugate was equally potent to free Dox, with improved specificity to breast cancer cell including Dox resistant cell lines. To accomplish the second goal, six MccJ25 peptide analogues were engineered. Peptides 1 and 6 displayed good activity against Salmonella newport. Peptide 1 displayed activity against five other Salmonella strains by inhibition of target cell respiration. Circular dichroism and proteases experiments showed that the active peptides adopt a folded structure but not the true lasso structure. Finally, a conjugate of MccJ25 peptide with 18-4 significantly enhanced the anticancer apoptotic activity in breast cancer cells by greater cellular uptake. Peptides identified herein are useful entities that can be translated to pharmacologically valuable structures of clinical value.
Language
English
DOI
doi:10.7939/R36D5PJ1P
Rights
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
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