Current cancer therapies have low specificity for tumor cells and have serious toxic side effects. Targeting drugs to the cancer cells can help improve the outcome of existing cancer therapies. In recent years, a number of peptides have been identified by peptide phage display for targeting different tumor types. Peptides identified from the phage display for targeting cancer cells can be further improved for specific binding and metabolic stability by chemical manipulation of their structures. The aims of this work were: (i) to develop a peptide array-whole cell binding assay for screening peptides with specific binding affinity for cancer cells (ii) design of novel peptidomimetics to improve their properties as drug candidates. First, peptide arrays based on the lead peptide sequences NGR and p160 were designed and synthesized. A direct peptide-cell binding assay using CyQUANT dye allowed identification of several new peptides with higher affinity for MDA-MB-435 and MCF-7 cancer cells compared to the wild type p160. These peptides did not recognize the normal endothelial HUVEC cells. Three p160 peptide analogues, namely, 11 (RGDPAYQGRFL), 18 (WXEAAYQRFL), and 40 (WXEPAYQRKL), that displayed highest affinity for the cancer cells were manually synthesized and labelled with FITC. The binding ability of these peptides was confirmed using fluorescence imaging and flow cytometry. The results confirmed the high and specific affinity of peptides 11 and 18 for the cancer cells. The peptide array-cell binding assay established in this study is not only useful for the identification of cancer targeting peptides. It can also be used for the generation of diagnostic tools for cancer. Secondly, two new classes of -peptides, 3- and 2-peptides derived from L-Asp and L-Dap monomers, respectively, were synthesized. The methodology allowed independent buildup of the -peptide backbone and the introduction of sequential side chain substitutions. It is shown that / mixed peptide increases target recognition and retains the proteolytic stability. Moreover, -peptides impart no cytotoxicity, which will expand their potential application in the design of biologically active peptides. As a result, these compounds represent good candidates for new drugs and as tools to gain further insight into protein folding and molecular recognition processes. / Pharmaceutical Sciences
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:AEU.10048/1272 |
| Date | 11 1900 |
| Creators | Ahmed, Sahar |
| Contributors | Dr. Kaur, Kamaljit (Faculty of Pharmacy and Pharmaceutical Sciences), Dr. Knaus, Edward Faculty of Pharmacy and Pharmaceutical Sciences, Dr. Pasutto,Franco Faculty of Pharmacy and Pharmaceutical Sciences, Dr. Velzquez,Carlos Faculty of Pharmacy and Pharmaceutical Sciences, Dr. Hall, Dennis Chemistry, Faculty of Science, Dr. Daneshtalab, Mohsen Pharmacy, Memorial University of Newfoundland |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | 6055602 bytes, application/pdf |
| Relation | S. Ahmed and K. Kaur, Proteolytic Cleavage of central /-Peptide Bond by Pronase and Trypsin. Chemical Biology & Drug Design, 2009, 73, 545., K. Kaur, T. Sprules, W. Soliman, R. Beleid, S. Ahmed, RightHanded 14-Helix in 3-Peptides from L-Aspartic Acid. Biochim. Biophys. Acta., 2008, 1784, 658., S. Ahmed, R. Beleid, T. Sprules, and K. Kaur, Solid-phase synthesis and CD spectroscopic investigations of novel -peptides from L-aspartic acid and -amino-L-alanine. Org. Lett., 2007, 9, 25. |
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