Amy Barrios
Assistant Professor of Medicinal Chemistry
B.S. University of Utah
Ph.D. Massachusetts Institute of Technology
Research
Research in the Barrios lab addresses topics at the interface between chemistry and biology, with an emphasis on exploring the chemical basis for the effects exerted by small molecules including metal ions in complex biological systems. In our work, we aim to provide a molecular understanding of both physiological and pathological processes with the ultimate goal of developing novel therapeutics for human diseases. Currently, we have two major projects in the lab:
Project #1: Probing the Substrate Specificity of Protein Tyrosine Phosphatases
Protein phosphorylation is crucial in many signaling pathways, and aberrant protein tyrosine phosphatase (PTP) activity has been implicated in a number of disease states including cancer, autoimmune disorders, diabetes mellitus and cardiovascular disease. We have recently developed a series of phosphotyrosine mimics that can be incorporated into peptide substrates and provide a highly sensitive fluorogenic assay for phosphatase activity. The novel probes that we are developing will be introduced into living cells and will allow imaging of tyrosine phosphorylation and dephosphorylation in vivo for the first time. Our future efforts will focus on using substrate libraries to design PTP-selective substrates and incorporating these fluorogenic substrates into cells for use as intracellular assays for enzyme activity and inhibition. The powerful tools under development in our lab will facilitate the study of tyrosine phosphorylation in cellular signaling under both physiological and pathological conditions.
Project #2: Investigating the Antiarthritic Activity of Au(I)
Gold has been used in the treatment of rheumatoid arthritis for over 80 years, but little is known about its mechanism of action. One intriguing possible target of gold in the body is the cathepsin family of lysosomal cysteine proteases; enzymes that are responsible for inflammation, extracellular matrix degradation and joint destruction in rheumatoid arthritis. We have been investigating the interactions of Au(I) with the cathepsin family of enzymes in order to gain insight into the biologically relevant coordination chemistry of gold. Current research efforts include elucidating the structure-activity relationship of the Au(I) complexes and developing chemical probes that can be used to pull down potential biological targets of Au(I) from complex biological mixtures. We are also working to obtain evidence that our Au(I) compounds inhibit enzyme activity in vivo as well as in vitro. Ultimately, our innovative interdisciplinary approach will provide an in-depth understanding of the principles governing Au(I)-biomolecule interactions, which will be used in the design of novel gold-based therapeutics.
References
1. 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., In Press
2. Gunatillek SS, Barrios AM (2008) Tuning the Au(I)-Mediated Inhibition of Cathepsin B Through Ligand Substitutions. J. Inorg. Biochem., In Press - special issue dedicated to CanBIC.
3. Mitra S, Barrios AM (2007) A Series of Peptide-Based, Fluorogenic Probes for Protein Tyrosine Phosphatase Activity. Anal. Biochem. 370:249-251
4. 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
5. Barrios AM(2006) Intracellular Metal Detectors. ACS Chem. Biol. 1(2):67-68
6. 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
7. 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
