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Assistant Professor of Medicinal Chemistry
Despite the therapeutic relevance of many human PTPs, our understanding of their biological substrates, substrate selectivity, cellular regulation and drug ability is limited. Research in the Barrios lab focuses on addressing these challenges through the development and application of novel chemical probes, specifically 1) using fluorogenic probes to investigate PTP activity and regulation during cellular signaling, 2) profiling the substrate selectivities of the PTP family of enzymes and 3) utilizing PTP substrate selectivity profiles in the design of potent, selective inhibitors and probes. We are particularly interested in PTPs involved in human autoimmunity and T-cell receptor signaling.
Imaging PTP activity: Cellular delivery of selective, fluorogenic PTP substrates will facilitate direct imaging of intracellular PTP activity and regulation. Novel sensors will be developed to probe the redox state of the enzymes, providing insight into regulatory mechanisms.
Profiling PTP substrate selectivity: Combinatorial phosphopeptide libraries will be used to profile the substrate selectivities of the PTPs with the goal of creating selective PTP substrates and inhibitors. Our initial focus is on proven therapeutic targets with homologs whose inhibition is undesirable, specifically the LYP/PEST pair (LYP is a target for human autoimmunity) and the PTP1B/TCPTP pair (targets for diabetes, obesity and cancer).
Probing PTP inhibition and regulation: By utilizing the information from substrate selectivity profiles, we will develop selective PTP inhibitors. Novel inhibitory motifs will provide both PTP-selective chemical “knock-outs” and activity-based probes. Intracellular high-throughput screening for PTP inhibitors using our novel probes will be a powerful tool in therapeutic PTP inhibitor development.