Date of Award

Spring 5-15-2017

Degree Type

Dissertation

Degree Name

PhD. Chemistry

Department

Chemistry and Biochemistry

Advisor

David Sabatino, Ph.D.

Committee Member

Wyatt R. Murphy, Ph.D.

Committee Member

Monika Raj, Ph.D.

Committee Member

Cecilia Marzabadi, Ph.D.

Keywords

Killer Peptide Nucleolipid Bioconjugates, Anti-Cancer Activity, Bioconjugation

Abstract

The killer peptide sequence D-(KLAKLAK)2 has been originally designed and developed as an antibacterial agent. Despite having excellent cytotoxicity towards bacteria, this sequence maintains low cell cytotoxity in malignant mammalian cell types such as cancer. The chemical basis for its selectivity has been attributed to its poly(cationic) amphiphilic nature, which facilitates cell permeability across the negatively charged bacterial membrane, but with limited permeability across the zwitterionic membrane of mammalian cells. The positively charged D-(KLAKLAK)2 sequence has been found to accumulate on the surface of the mitochondria causing dissipation of the negatively charged mitochondrial membrane potential. This charge disruption results in membrane lysis and the secretion of cell death markers that ultimately lead to programmed cell death. In order to overcome the limited activity of the D-(KLAKLAK)2 sequence in malignant tumor cell types, we proposed that chemically robust and structurally pre-organized amphiphilic nucleolipids would function to enhance cell permeability and mitochondria localization in tumors, resulting in potent and long-lasting anti-cancer effects. In this study, thymidine-derived nucleolipids were rationally designed to contain 3’-lipid appendages and a reactive 5’-carboxy group. A diversity oriented synthesis approach featuring a reductive amination procedure was developed for making a small library of amphiphilic nucleolipids. Solid phase bioconjugation coupled the nucleolipids with the pro-apoptotic D-(KLAKLAK)2 sequence for exploring structure-activity relationships. The peptide nucleolipid conjugates were found to self-assemble into amphiphilic nanoparticle formulations that promoted anti-cancer activity in a selected panel of cancer cells. This thesis will serve to highlight the most important findings towards the development of peptide-nucleolipid conjugates that effectively serve as potent anti-cancer agents.

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