Amy Barrios
Assistant Professor of Medicinal Chemistry
B.S. University of Utah
Ph.D. Massachusetts Institute of Technology
Amy Barrios' PubMed Literature Search
Research
Despite the therapeutic relevance of many human PTPs, our understanding of their biological substrates, substrate selectivity, cellular regulation and druggability 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.
References
1. Krishnamurthy D, Karver MR, Fiorillo E, Orru V, Stanford SM, Bottini N, Barrios AM (2008) Gold(I)-Mediated Inhibition of Protein Tyrosine Phosphatases: A detailed in vitro and cellular study. J. Med. Chem. 51(15):4790-5
2. Mitra S, Barrios AM (2008) Identifying Selective Protein Tyrosine Phosphatase Substrates and Inhibitors from a Fluorogenic, Combinatorial Peptide Library. ChemBioChem 9(8)1216-1219
3. Franzman MA, Barrios AM (2008) Spectroscopic Evidence for the Formation of Goldfingers. Inorg. Chem. 47:3928-3930
4. Gunatilleke SS, de Oliviera CAF, McCammon JA, Barrios AM (2008) Inhibition of Cathepsin B by Au(I) Complexes: A Kinetic and Computational Study. J. Biol. Inorg. Chem. 13(4)555-561
5. Hubbard CE, Barrios AM (2008)A Highly Efficient Route to Enantiomerically Pure l-N-Bz-Pmp(t-Bu)2-OH and Incorporation into a Peptide-Based Protein Tyrosine Phosphatase Inhibitor. Bioorg. Med. Chem. Lett. 18(2):679-81
6. Gunatillek SS, Barrios AM (2008) Tuning the Au(I)-Mediated Inhibition of Cathepsin B Through Ligand Substitutions. J. Inorg. Biochem. 102(3):555-63
7. Mitra S, Barrios AM (2007) A Series of Peptide-Based, Fluorogenic Probes for Protein Tyrosine Phosphatase Activity. Anal. Biochem. 370:249-251
8. Gunatilleke SS, Barrios AM (2006)Inhibition of Lysosomal Cysteine Proteases by Au(I) Compounds: A Detailed Mechanistic Investigation. J. Med. Chem. 49(13):3933-3937
9. Barrios AM(2006) Intracellular Metal Detectors. ACS Chem. Biol. 1(2):67-68
10. Mitra S. Barrios AM (2005) Highly Sensitive Peptide-Based Probes for Protein Tyrosine Phosphatase Activity Utilizing a Fluorogenic Mimic of Phosphotyrosine. Bioorg. Med. Chem. Lett. 15:5142-5145
11. Chircorian A, Barrios AM (2004) Inhibition of Lysosomal Cysteine Proteases by Chrysotherapeutic Compounds: A Possible Mechanism for the Antiarthritic Activity of Au(I). Bioorg. Med. Chem. Lett. 14:5113-5116
