Understanding the roles of conformational constraints in functional phosphotyrosine mimics

Tufts University, Medford MA

Investigators

Abstract

With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Joshua Kritzer of Tufts University to explore the structures and functions of molecules that affect phosphotyrosine signaling. In all higher organisms, important signals for cell growth and function are mediated by phosphotyrosine. While some of the proteins involved in phosphotyrosine signaling can be inhibited using small molecules, most are difficult for chemists to target. In this project, the Kritzer group will use new, structurally complex molecules to attempt to modulate the activity of phosphotyrosine-signaling proteins in vitro and in living cells. Understanding the structures and functions of these molecules is expected to advance our ability to design molecules with useful function, and our knowledge of how such molecules interact with living systems. Graduate students and undergraduates participating in this project will also participate in grade school workshops focused on teaching the scientific method using microbes. While there are many useful and selective inhibitors available for blocking tyrosine kinases, there are almost no useful inhibitors for the other components of phosphotyrosine signaling, namely SH2 domains and tyrosine phosphatases. Traditional approaches to inhibiting these proteins use phosphotyrosine isosteres, which improve affinity at the cost of low selectivity and poor cell uptake. By contrast, successive constraints within a non-phosphorylated peptide produce molecules that mimic phosphotyrosine via their conformation. This produces inhibitors with simultaneous improvements in affinity, selectivity, metabolic stability, and cellular uptake. Small, highly constrained peptides are a promising source for inhibitors of SH2 domains and tyrosine phosphatases, which would have direct applications in many aspects of cell biology. If the findings can be generalized, it may be possible to target a range of protein-protein interactions with this strategy.