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Abstract

Protein-protein interactions (PPIs) are critical to nearly all cellular functions. Despite more than 30 years of research detailing the impacts of specific PPIs in disease, there remain numerous undruggable interactions that lead to negative health outcomes. A major complication in the field of PPIs is understanding how multiprotein networks and complexes interact with one another over time. In particular, one challenge is a lack of methods to study the selective inhibition of one PPI vs. several others in a native cellular context. Another challenge is a lack of tools to selectively induce two proteins to interact with one another, enabling the control of cellular functions. In this thesis, I begin by discussing the character and importance of PPIs. I then detail a proof-of-concept method to study PPI networks and their selective inhibition in live mammalian cells, including a practical guide for using this method and expanding its use in the future. Finally, I describe a new directed evolution method for the rapid evolution of protein-protein interaction glues (rePPI-G) that is capable of evolving bivalent PPI inducers within a matter of days. Development of this new method also resulted in observations about optimal bivalent ligand design, presaging utility of the principles for optimizing small molecule bivalent glues. It is my hope that this work will catalyze new methodologies focused on modifying and studying multiprotein systems, which in turn fuels advancements in pharmacological tools to understand and treat human disease.

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