B.S. 1995, Chemistry, University of Utah
Ph.D. 2000, Massachusetts Institute of Technology. Mentor: Stephen J. Lippard
2000-2003, Department of Pharmaceutical Chemistry, University of California, San Francisco, NIH Postdoctoral Fellow. Mentor: Charles S. Craik
Chemical probes for visualizing PTP activity
Protein tyrosine phosphatases (PTPs) play critical roles in cellular signaling, regulating tyrosine phosphorylation through hydrolysis of the tyrosine phosphate in a temporally, spatially and regioselectively controlled manner. In contrast to their counterparts, the protein tyrosine kinases (PTKs), the substrate selectivity, biological regulation and specific roles of PTPs are relatively poorly understood. However, aberrant phosphotyrosine-dependent cellular signaling plays an important role in many human diseases, including cancer, diabetes and autoimmunity. PTK-targeted drugs have hit the market with considerable success as anticancer agents, but no PTP-targeted drugs have been developed to date. In this project, our aim is to develop novel PTP-targeted chemical probes that can be used to elucidate the biological roles of PTPs and can serve as lead compounds in the development of PTP-targeted therapeutics. For example, we designed the phosphocoumaryl amino acid pCAP as a fluorogenic phosphotyrosine mimic. This probe has been invaluable in allowing us to profile the substrate selectivity of PTPs, perform several high-throughput screens to identify novel PTP inhibitors, and visualize PTP activity both directly in cells and in cell lysates through polyacrylamide gel electrophoresis. Current work includes characterizing and optimizing the new inhibitors we have discovered and developing novel activity-based probes for PTPs.
Understanding the biological action of metal-based drugs
While the majority of drug molecules are organic compounds, several very successful drugs contain metal ions. Certainly the most well-know (and well-studied) example is cisplatin, a platinum containing anticancer agent, but other examples include auranofin, a gold-containing antiarthritic agent; Pepto-BismolÂ®, a bismuth-containing treatment for gastrointestinal problems; and imaging agents such as magnevist (a gadolinium-based MRI contrast agent) and cardiolyte (a technetium-based radioimaging agent). In our lab, we have been studying the ability of auranofin and auranofin analogs to inhibit enzyme activity as one possible mechanism of action in the body. Au(I)-based compounds such as auranofin inhibit thiol-dependent enzymes, and we have demonstrated that, by tuning the ligands bound to the Au(I) ion, we can tune the selectivity and potency of the Au(I)-mediated inhibition. The relative potencies and selectivities of the new complexes hold up not only in vitro but also in vivo.
Designing redox sensors
A recent area of emphasis for our lab is the development of fluorogenic chemical probes that can be used to image the production of redox active species in vivo. Our first efforts in this field are aimed at developing hydrogen peroxide sensors that can be delivered to a specific subcellular location (i.e. the cell surface, the cytosol, the mitochondria, etc.) and at developing hydrogen sulfide sensors based on fluorogenic organometallic compounds.
Research Group Members
Suvendu Biwas, Ph.D.
Suvendu’s current work focuses on developing selective substrates for monitoring protein tyrosine phosphatase activity. As a researcher, he uses his skills as a medicinal chemist to develop tools to study protein tyrosine phosphatase enzymes. These enzymes are critical in cellular signaling pathways and are important therapeutic targets for the treatments of human diseases including diabetes, autoimmunity, and cancer. This signaling process is highly controlled by the tandem actions of protein tyrosine kinase (PTKs) and protein tyrosine phosphatases (PTPs).
Although there are over a dozen PTK inhibitors currently used as drugs there are no targeted PTP inhibitors that have successfully completed clinical trials. Considering the high importance of the PTPs and their roles in many cellular processes; development of a rapid, sensitive, and fluorogenic probe is highly desirable. His current projects include: Near-IR PTP substrate design: Near infrared (NIR) fluorescence imaging is an emerging field for monitoring enzymatic activity in the living organism. The development of new fluorescent imaging sensors had a great impact on detecting and monitoring enzymatic activity in living cells. He is currently working on design and synthesis of long-wavelength water soluble fluorogenic and colorimetric substrate for monitoring protein tyrosine phosphatase enzymes.
DNA-encoded substrate library design: DNA-encoded chemical libraries represent an effective tool for drug discovery. Using this technology, a large number of chemical libraries can easily be accessed and screened at decent costs. In this current work, the assembly of the DNA-encoded substrate library is being used to find selective substrate to target PTPs. The library will be used for high-throughput inhibitor screening. This work is being carried out in collaboration with Prof. Raphael Franzini Lab, one of the leading experts in the DNA-encoded library design.
Alongside postdoctoral research, he also has a strong interest in technology, leadership, and management. He is a professional MBA candidate at the University of Utah - David Eccles School of Business. In his free time, he loves hiking, playing soccer and visiting new places.
Elena Shuangyu Ma
Protein tyrosine phosphatases (PTP) are intriguing therapeutic targets for the prevention and treatment of autoimmunity, diabetes, cancer, and other common human diseases. I have been working on developing cell permeable PTP specific activity-based chemical probes to help understand the activities and regulation of different PTPs both in vitro and in vivo.
Other Current Members
Brandon S. McCullough
Dr. Vanessa Ahmed Ph.D. - University of Waterloo - Postdoc 2010-2013
Dr. Ryan Mathews Ph.D. - University of Buffalo 2008 - Postdoc 2008-2010 - Senior Field Specialist, Metrohm
Dr. Divya Krishnamurthy Ph.D. - Johns Hopkins University, 2006 - Postdoc 2006-2008, Research Assistant Professor 2008-2010 - Safety Partners, Inc.
Dr. Christopher Dollberg Ph.D. - Ohio State University, 2004 - Postdoc 2004-2005 - Program Manager, Security Feature Development, Bureau of Engraving and Printing
Megan Thorson Youmans Ph.D. - Medicinal Chemistry, University of Utah, 2014 - Postdoc Boston University, 2015-2016 - Assistant Professor of Chemistry, Wilkes College, PA
Rhushikesh Kulkarni Ph.D. - Medicinal Chemistry, University of Utah 2013 - Postdoctoral researcher, National Cancer Institute
Caitlin Hubbard Karver Ph.D. - Chemistry, University of Southern California, 2009 - Postdoc Northeastern University - Associate Professor of Chemistry, DePaul University, Il
Teodora Kaltcheva Ph.D. - Chemistry, University of Southern California, 2009 - Postdoc City of Hope, Duarte, CA - Instructor, UCLA
Mark Karver Ph.D. - Chemistry, University of Southern California, 2009 - Postdoc, Massachusetts General Hospital - Director, Peptide synthesis core facility, Northwestern University
Shamila Gunatilleke (Nadir) Ph.D. - Chemistry, University of Southern California, 2007 - Postdoc, UCI, UCSF - Lecturer, Seattle University
Sayantan Mitra Ph.D. - Chemistry, University of Southern California, 2007 - Postdoc, Sanford-Burnham Institute for Medical Research - Scientist II, Clontech
Stephanie Koenig M.A. in Chemistry - University of Southern California, 2007
Oxana Sergienko M.A. in Chemistry - University of Southern California, 2005
If you are interested in joining the Barrios lab, please contact Dr. Barrios by email. Potential postdoctoral researchers should have a strong background in synthetic chemistry, chemical biology or enzymology. Potential Ph.D. students are encouraged to apply though the Biological Chemistry Graduate Program. Undergraduates interested in gaining research experience are welcome.
- “A luminogenic lanthanide-based probe for the highly selective detection of nanomolar sulfide levels in aqueous samples” M. L. Aulsebrook, S. Biswas, F. M. Leaver, M. R. Grace, B. Graham, A. M. Barrios, K. L. Tuck Chem. Commun. 2017, 53, 4911-4914.
- “Dual Colorimetric and Fluorogenic Probes for Visualizing Tyrosine Phosphatase Activity and High Throughput Screening” S. Biswas, B. S. McCullough, C. W. Russell, D. G. Brown, J. L. Round, M. A. Mulvey, A. M. Barrios Chem. Commun. 2017, 53, 2233-2236.
- “Lanthanide complexes as luminogenic probes to measure sulfide levels in industrial samples” M. K. Thorson, P. Ung, F. M. Leaver, T. S. Corbin, K. L. Tuck*, B. Graham*, A. M. Barrios* Anal. Chim. Acta 2015, 896, 160-165.
- “Marine Natural Products as Inhibitors of Cystathionine beta-Synthase Activity” M. K. Thorson, R. M. Van Wagoner, M. K. Harper, C. M. Ireland, T. Majtan, J. P. Kraus, A. M. Barrios Bioorg. Med. Chem. Lett. 2015, 25, 1064-1066.
- “Early Endosomal Escape of a Cyclic Cell-Penetrating Peptide Enables Effective Cytosolic Cargo Delivery” Z. Qian, J. LaRochelle, B. Jiang, W. Lian, R. Hard, N. G. Selner, R. Leuchapanichkul, A. M. Barrios, D. Pei Biochem. 2014 53(24), 4034-4046.
- “Inhibition of the Lymphoid Tyrosine Phosphatase: The Effect of Zinc(II) ions and Chelating Ligand Fragments on Enzymatic Activity” M. K. Thorson, D. T. Puerta, S. M. Cohen, A. M. Barrios Bioorg. Med. Chem. Lett. 2014 24(16), 4019-4022.
- “Auranofin is an Apoptosis Stimulating Agent with in vitro and in vivo Anti-Leishmanial Activity” E. Sharlow, S. Leimgruber, S. Murray, A. Lira, R. Sciotti, M. Hickman, T. Hudson, S. Leed, D. Caridha, A. M. Barrios, D. Close, M. Grogl, J. Lazo ACS Chem. Biol. 2014 9(3), 663-672.
- “Monitoring Intracellular Protein Tyrosine Phosphatase Activity” S. M. Stanford, V. F. Ahmed, N. Bottini, A. M. Barrios Antioxidants and Redox Signaling 2014 20(14), 2160-2178.
- “Covalent Inhibition of the Lymphoid Tyrosine Phosphatase” V. F. Ahmed, N. Bottini & A. M. Barrios ChemMedChem 2014 9(2), 296-299.
- “pCAP-Based Peptide Substrates: The New Tool in the Box of Tyrosine Phosphatase Assays” S. M. Stanford, D. Krishnamurthy, C. E. Karver, E. Bruenger, L. Walker, C.-T. Ma, T. D. Y. Chung, E. Sergienko, N. Bottini, A. M. Barrios Methods 2014 65, 165-174.
- “Substrate Selection Influences Molecular Recognition in a Screen for Lymphoid Tyrosine Phosphatase Inhibitors” R. A. Kulkarni, N. A. Vellore, M. R. Bliss, S. M. Stanford, M. D. Falk, N. Bottini, R. Baron, A. M. Barrios ChemBioChem 2013 14(13), 1640-1647.
- “Thiuram Disulfides as Irreversible Inhibitors of the Lymphoid Tyrosine Phosphatase” R. A. Kulkarni, S. M. Stanford, N. A. Vellore, M. R. Bliss, D. Krishnamurthy, R. Baron, N. Bottini, A. M. Barrios ChemMedChem 2013 8(9), 1561-1568.
- “Medicinal Inorganic Chemistry: a web themed issue” A. M. Barrios, S. M. Cohen, M. H. Lim Chem. Commun. 2013 49, 5910-5911
- “A Potent and Selective Small Molecular Inhibitor for the Lymphocyte-Specific Tyrosine Phosphatase (LYP), a Common Risk Factor Associated with Autoimmune Diseases” Y. He, S. Liu, A. Menon, S. M. Stanford, E. Oppong, A. M. Gunawan, L. Wu, A. M. Barrios, N. Bottini, A. C. B. Cato, Z.-Y. Zhang J. Med. Chem, 2013 56(12) 4990-5008.
- “Identification of Cystathionine beta-Synthase Inhibitors Using a Novel Hydrogen Sulfide Selective Probe” M. K. Thorson, T. Majtan, J. P. Kraus, A. M. Barrios Angew. Chem. 2013 52, 4641-4644.
- “Efficient Delivery of Cyclic Peptides into Mammalian Cells with Short Sequence Motifs” Z. Qian, T. Liu, Y.-Y. Liu, R. Briesewitz, A. M. Barrios, S. M. Jhiang, D. Pei ACS Chem. Biol. 2013 8(2), 423-431.
- “High-Throughput Screen Using a Single-Cell Tyrosine Phosphatase Assay Reveals Biologically Active CD45 Inhibitors” S. M. Stanford, R. G. Panchal, L. M. Walker, M. D. Falk, S. Mitra, S. S. Damle, D. Ruble, T. Kaltcheva, S. Zhang, Z.-Y. Zhang, S. Bavari, A. M. Barrios, N. Bottini Proc. Natl. Acad. Sci. 2012, 109(35), 13972-13977.
- “A High-Throughput Drug Screen for Entamoeba histolytica identifies a new lead and target” A. Debnath, D. Parsonage, R. Andrade, C. He, E. Cobo, K. Hirata, S. Chen, G. Garcia-Rivera, E. Orozco, M. Martinez, S. Gunatilleke, A. M. Barrios, M. Arkin, L. Poole, J. McKerrow, S. Reed Nat. Med. 2012, 18(6), 956-960.
- “PEST-Domain-Enriched Tyrosine Phosphatase and Glucocorticoids as Regulators of Anaphylaxis in Mice.” D. Obiri, N. Flink, J. Maier, A. Neeb, D. Maddalo, W. Thiele, A. Menon, M. Stasson, R. Kulkarni, M. Garabedian, A. M. Barrios, A. Cato Allergy 2012, 67, 175-182.
- “Discovery of a Novel Series of Inhibitors of Lymphoid Tyrosine Phosphatase with Activity in Human T Cells” S. Stanford, D. Krishnamurthy, M. Falk, R. Messina, B. Debnath, S. Li, T. Liu, R. Kazemi, R. Dahl, Y. He, X. Yu, A. Chan, Z.-Y. Zhang, A. M. Barrios, V. Woods, N. Neamati, N. Bottini J. Med. Chem. 2011 54, 1640-1654.
- “Oxidative Inactivation of the Lymphoid Tyrosine Phosphatase Mediated by Both General and Active Site Directed NO Donors” C. E. Karver, V. F. Ahmed and A. M. Barrios Bioorg. Med. Chem. Lett. 2011 21, 285-287.
- “Gold(I) Phosphine-Mediated, Selective Inhibition of Lymphoid Tyrosine Phosphatase” M. R. Karver, D. Krishnamurthy, N. Bottini and A. M. Barrios J. Inorg. Biochem. 2010 104(3) 268-273.
- “Identifying Potent, Selective Protein Tyrosine Phosphatase Inhibitors from a Library of Au(I) Complexes” M. R. Karver, D. Krishnamurthy, R. Kulkarni, N. Bottini and A. M. Barrios J. Med. Chem. 2009 52, 6912-6918.
- “Profiling Protein Tyrosine Phosphatase Activity with Chemical Probes” D. Krishnamurthy and A. M. Barrios Curr. Opin. Chem. Biol. 2009 13, 375-381 (invited review).
- “Identifying and Characterizing the Biological Targets of Metallotherapeutics: Two approaches using Au(I)-protein interactions as model systems” M. R. Karver and A. M. Barrios, Anal. Biochem. 2008 382, 63-65.
- “Gold(I)-Mediated Inhibition of Protein Tyrosine Phosphatases” D. Krishnamurthy, M. R. Karver, E. Fiorillo, V. Orru, S. M. Stanford, N. Bottini and A. M. Barrios, J Med. Chem. 2008, 51, 4790-4795.
- “Spectroscopic Evidence for the Formation of Goldfingers” M. A. Franzman and A. M. Barrios, Inorg. Chem. 2008 47, 3928-3930.
- “Identifying Selective Protein Tyrosine Phosphatase Substrates and Inhibitors from a Fluorogenic, Combinatorial Peptide Library” S. Mitra and A. M. Barrios, ChemBioChem 2008, 9(8), 1216-1219.
- “Inhibition of Cathepsin B by Au(I) Complexes: A Kinetic and Computational Study” S. S. Gunatilleke, C. A. F. de Oliviera, J. A. McCammon and A. M. Barrios, J. Biol. Inorg. Chem. 2008, 13(4), 555-561.
- “Tuning the Au(I)-Mediated Inhibition of Cathepsin B Through Ligand Substitutions” S. S. Gunatilleke and A. M. Barrios J. Inorg. Biochem. 2008, 102, 555-563 (special issue dedicated to CanBIC).
- “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” C. E. Hubbard and A. M. Barrios, Bioorg. Med. Chem. Lett. 2008 18, 679-681.
- “A Series of Peptide-Based, Fluorogenic Probes for Protein Tyrosine Phosphatase Activity” S. Mitra and A. M. Barrios Anal. Biochem. 2007, 370, 249-251
- “Inhibition of Lysosomal Cysteine Proteases by Au(I) Compounds: A Detailed Mechanistic Investigation” S. S. Gunatilleke and A. M. Barrios J. Med. Chem. 2006, 49(13), 3933-3937.
- “Intracellular Metal Detectors” A. M. Barrios ACS Chem. Biol. 2006, 1(2), 67-68.
- “Highly Sensitive Peptide-Based Probes for Protein Tyrosine Phosphatase Activity Utilizing a Fluorogenic Mimic of Phosphotyrosine” S. Mitra and A. M. Barrios Bioorg. Med. Chem. Lett. 2005, 15, 5142-5145.
- “Inhibition of Lysosomal Cysteine Proteases by Chrysotherapeutic Compounds: A Possible Mechanism for the Antiarthritic Activity of Au(I).” A. Chircorian and A. M. Barrios Bioorg. Med. Chem. Lett. 2004, 14, 5113-5116.
- "Scanning the Prime-Site Substrate Specificity of Proteolytic Enzymes: A Novel Assay Based on Ligand-Enhanced Lanthanide Ion Fluorescence." A. M. Barrios and C. S. Craik, Bioorg. Med. Chem. Lett., 2002, 12, 3619-3623.
- "Decomposition of Alkyl-Substituted Urea Molecules at a Hydroxide-Bridged Dinickel Center." A. M. Barrios and S. J. Lippard. Inorg. Chem. 2001, 40, 1250-1255.
- "Phthalazine-Based Dinucleating Ligands Afford Dinuclear Centers Often Encountered in Metalloenzyme Active Sites." A. M. Barrios and S. J. Lippard. Inorg. Chem. 2001, 40, 1060-1064.
- "Diiron Complexes of 1,8-Naphthyridine-Based Dinucleating Ligands as Models for Hemerythrin." C. He, A. M. Barrios, D. Lee, J. Kuzelka, R. M. Davydov and S. J. Lippard. J. Am. Chem. Soc. 2000, 122, 12683-12690.
- "Interaction of Urea with a Hydroxide-Bridged Dinuclear Nickel Center: An Alternative Model for the Mechanism of Urease." A. M. Barrios and S. J. Lippard. J. Am. Chem. Soc. 2000, 122, 9172-9177.
- "Amide Hydrolysis Effected by a Hydroxo-Bridged Dinickel(II) Complex: Insights into the Mechanism of Urease." A. M. Barrios and S. J. Lippard. J. Am. Chem. Soc. 1999, 121, 11751-11757.
- "The Reactivity of Well Defined Diiron(III) Peroxo Complexes Toward Substrates: Addition to Electrophiles and Hydrocarbon Oxidation." D. D. LeCloux, A. M. Barrios and S. J. Lippard. Bioorg. Med. Chem. 1999, 7, 763-772.
- "Modeling the Diiron Centers of Non-Heme Iron Enzymes. Preparation of Sterically Hindered Diiron(II) Tetracarboxylate Complexes and Their Reactions with Dioxygen." D. D. LeCloux, A. M. Barrios, T. J. Mizoguchi and S. J. Lippard. J. Am. Chem. Soc. 1998, 120, 9001-9014.
- "Synthesis of 2-Alkyl-3-Hydroxy-4-Pyridinone-Ribonucleosides, Potential Oral Iron Chelators." G. Liu, F. W. Bruenger, A. M. Barrios, S. C. Miller. Nucleosides and Nucleotides 1995, 14, 1901-1904.
- “Coumarin Based Amino Acids for Use in Enzyme Activity and Substrate Assays” S. Mitra and A. M. Barrios. United States Patent Number 9,045,507, granted June 2, 2015
- “Method for Monitoring Intracellular Tyrosine Phosphatase Activity” N. Bottini, S. M. Stanford, A. M. Barrios and S. Mitra. United States Patent Number 8,399,213, granted March 19, 2013.
- “Compositions and Methods for Determining Substrate Specificity of Hydrolytic Enzymes” A. M. Barrios and C. S. Craik. United States Patent Application Number 20050207981.