Bicyclic Peptides as Inhibitors of Protein-Protein Interactions: The development of conformational phosphotyrosine mimetics.
Abstract: 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 o... read moref 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.
Thesis (Ph.D.)--Tufts University, 2015.
Submitted to the Dept. of Chemistry.
Advisor: Joshua Kritzer.
Committee: Joshua Kritzer, Clay Bennett, Elena Rybak-Akimova, and Jianmin Gao.
Keyword: Chemistry.read less