Bicyclic Peptides as Inhibitors of Protein-Protein Interactions: The development of conformational phosphotyrosine mimetics

The interactions that occur between proteins in a living system dictate many vital cellular events, and the proper control of the onset and duration of these intermolecular interactions is critical for healthy cellular activity. The aberrant regulation of protein-protein interactions has been correlated with a variety of human pathologies, and the development of chemical modulators of these interactions has therefore become the focus of a variety of medicinal chemistry campaigns. However, harvesting therapeutic lead compounds capable of antagonizing protein-protein interactions from libraries of traditional small molecules has often been challenging. Traditional small molecules represent an area of chemical space that is structurally ill-equipped for disrupting such interactions, as these compounds frequently lack the sheer size necessary to achieve a high target affinity and to discriminate among the binding pockets of similar proteins. Larger species, such as whole proteins and other biologic agents, often overcome this obstacle at the expense of poor bioavailability and metabolic stability. As a result, many protein-protein interactions have been historically intractable targets.;The work discussed herein represents an effort to target two such problematic protein-protein interactions that have been implicated in a diversity of human disease states. This work is unique in its approach, as we sought to discover and characterize inhibitors of these protein-protein interactions from a region of chemical space with physicochemical properties intermediate between those of traditional small molecules and large biologics. The work discussed in this dissertation concerns the discovery, development and structural characterization of constrained peptide scaffolds that uniquely mimic phosphotyrosine so as to antagonize the interactions of the Grb2-SH2 domain and PTP1B. This dissertation also details the cell-penetrating capabilities of these novel peptides, as well as the atomic-level details that dictate phosphotyrosine mimicry and cellular internalization. The strategy presented herein represents an application of a potentially broad paradigm for targeting phosphotyrosine-binding proteins, and efforts remain underway to continue to use this technology for the discovery of chemical modulators of a wide variety of other phosphotyrosine-mediated protein-protein interactions.