BIOLOGICAL PEPTIDE INTERACTIONS  WITH CELLULAR MEMBRANES

Brandan Michael Cook

Eukaryotic cell membrane dynamics change in curvature during physiological and pathological processes. These processes cause dynamic membrane changes leading to seven important cellular biological functions, which include endocytosis, phagocytosis, filopodium, lamellipodium, cytokinesis, adhesion, and podosome formation, via distinct signaling pathways determined by specific domain binding partners. These cellular processes are also heavily dictated by intrinsic proteins that modulate transfer of extracellular materials, regulate cell trafficking and mobility, present antigens, mediate extracellular matrix degradation, and transmit proliferation signals. The extracellular vesicles (EVs) that facilitate the transfer of biomolecules are membrane derived fat-bubbles released by cells, made primarily of phospholipids that form a bilayer. EVs heavily participate in cellular communication through the processes of cell-to-cell contact and/or secretion of soluble bioactive-molecules. This dissertation touches on the topic of the similarities and differences between EVs and liposomes with the focus on features that are relevant for lipid vesicle isolation as well as drug delivery purposes such as circulation time, biodistribution, cellular interactions and cargo loading. Currently, Immunoaffinity is the traditional method of EV detection, but is inherently limited by protein expression. To surmount this, a mini-library of synthetic peptides were designed to target common properties of EV membranes. This work also reports on trimeric peptides prepared from a Bradykinin derivative that preferentially bind to highly curved surfaces of both synthetic lipid vesicles and exosomes from cultured cancer cell lines. The peptide-membrane interaction studies mentioned above opened the research doors to a Prostate cancer (PCa) peptide-transmembrane domain (TMD) inhibition study. PCa is the second leading cause of cancer-related deaths among American males. The high expression of a membrane protein called Prostate Specific Membrane Antigen (PSMA) is implicated in PCa invasiveness as well as neovasculature of nonprostatic solid tumors. Further, it is widely recognized that many membrane proteins participate in intracellular signal transduction through the lateral association of their TMDs, but this has not been directly demonstrated in PSMA. Thus, we aimed to determine if the TMD could be perturbed by engineered synthetic peptides.

BIOLOGICAL PEPTIDE INTERACTIONS WITH CELLULAR MEMBRANES

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