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You searched for +publisher:"University of Southern California" +contributor:("Barrios, Amy M."). Showing records 1 – 3 of 3 total matches.

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University of Southern California

1. Mitra, Sayantan. Development, synthesis and applications of highly sensitive fluorescent probes for studying protein tyrosine phosphatases.

Degree: PhD, Chemistry, 2009, University of Southern California

Protein tyrosine phosphatases (PTPs) constitute an important class of enzymes that are involved in various cellular processes such as mitogenesis, cell growth, signal transduction, immune response and gene transcription. PTP targeted therapeutics have been slow to develop in part, because the substrate selectivity of the PTPs is not well understood and also due to unavailability of suitable probes to study PTP selectivity. Herein is described the design and synthesis of highly fluorescent probes that provide a highly sensitive, continuous assay for PTP activity and are readily incorporated into peptide substrates for high-throughput screening or activity-based assays. These probes are efficiently hydrolyzed by PTPs of both human and bacterial origin. The fluorogenic probe pCAP, was further used to synthesize positional-scanning synthetic combinatorial libraries (PS-SCL) of peptide substrates in order to determine the extended substrate specificities of various PTPs. Such a profile of substrate specificities readily shows both the similarities and differences between PTPs of the same family and those of different families. Furthermore, it was observed that replacing the fluorogenic probe in selective substrates with non hydrolyzable mimics of phosphotyrosine could result in potent, selective inhibitors. The substrate specificities determined from this study would be invaluable in the design of potent, selective PTP substrates and inhibitors for biochemical and therapeutic applications. Furthermore, these probes were used to design peptides for cellular imaging. The viability of the imaging principle using coumarin based probes was checked and various conditions for optimizing internalization of the peptides in cells were analyzed. The imaging technique would allow one to carry out high throughput screening for drugs in cells, and will have a wide impact on the fields of drug development and drug discovery. Advisors/Committee Members: Barrios, Amy M. (Committee Chair), Bottini, Nunzio (Committee Member), Prakash, G.K. Surya (Committee Member).

Subjects/Keywords: fluorescence; protein tyrosine phosphatases; coumarin; fluorescent amino acids; PTP substrate selectivity; substrate specificity; selective PTP inhibitors; cellular imaging

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APA (6th Edition):

Mitra, S. (2009). Development, synthesis and applications of highly sensitive fluorescent probes for studying protein tyrosine phosphatases. (Doctoral Dissertation). University of Southern California. Retrieved from http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/518695/rec/1969

Chicago Manual of Style (16th Edition):

Mitra, Sayantan. “Development, synthesis and applications of highly sensitive fluorescent probes for studying protein tyrosine phosphatases.” 2009. Doctoral Dissertation, University of Southern California. Accessed January 21, 2020. http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/518695/rec/1969.

MLA Handbook (7th Edition):

Mitra, Sayantan. “Development, synthesis and applications of highly sensitive fluorescent probes for studying protein tyrosine phosphatases.” 2009. Web. 21 Jan 2020.

Vancouver:

Mitra S. Development, synthesis and applications of highly sensitive fluorescent probes for studying protein tyrosine phosphatases. [Internet] [Doctoral dissertation]. University of Southern California; 2009. [cited 2020 Jan 21]. Available from: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/518695/rec/1969.

Council of Science Editors:

Mitra S. Development, synthesis and applications of highly sensitive fluorescent probes for studying protein tyrosine phosphatases. [Doctoral Dissertation]. University of Southern California; 2009. Available from: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/518695/rec/1969


University of Southern California

2. Gunatilleke, Shamila S. Inhibition of cysteine proteases by Au(I) complexes: a kinetic and mechanistic investigation.

Degree: PhD, Chemistry, 2007, University of Southern California

Rheumatoid arthritis (RA) is an inflammatory and disabling joint disease affecting approximately 2.5 million people in the United States. Although it has been classified as an autoimmune disorder its etiology remains unknown. Due to the complex nature of the disease a proper treatment have been difficult to find. There are several clinically available gold(I) salts as drugs to treat RA. However, to date, an understanding of the chemistry behind it's therapeutic effect is not available. Gold is known to be thiophilic and found to undergo facile ligand exhange reactions with biological thiolates like cysteines, especially those with low pKa values. The cathepsin family of lysosomal cysteine proteases are likely targets of gold because they are implicated in RA, found to localized in arthritic joints, and are cysteine dependant. In order to investigate the cathepsin inhibition as a biological relevant chemistry of gold, a series of linear two coordinated gold(I) complex analogs of auranofin have been synthesized, characterized and their effect on human cathepsin B activity tested. The role of steric and electronic effects of the phosphine ligands on these complexes was investigated. Molecular modeling studies were performed to understand the gold(I)-biomolecule interaction in depth. Selectivity of these complexes for cathepsin B over other cysteine dependant enzymes tested. The complexes were found to inhibit human cathepsin B competitively and reversibly with IC50 values ranging from nanomolar to micromolar. Computational and experimental results suggested that favorable interactions of the inhibitor and the enezyme are critical to the efficiency of the inhibitor. Both electronic and steric effects of the phosphine ligand were found to play crucial roles in the potency of inhibitors. Highly potent gold(I) inhibitors of cathepsin B show selectivity towards it over other cysteine dependant enzymes. Advisors/Committee Members: Barrios, Amy M. (Committee Chair), Thompson, Mark E. (Committee Member), Baudry, Michel (Committee Member).

Subjects/Keywords: gold complexes; enzyme inhibition; cathepsin; rheumatoid arthritis; proteases

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Gunatilleke, S. S. (2007). Inhibition of cysteine proteases by Au(I) complexes: a kinetic and mechanistic investigation. (Doctoral Dissertation). University of Southern California. Retrieved from http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/529088/rec/3494

Chicago Manual of Style (16th Edition):

Gunatilleke, Shamila S. “Inhibition of cysteine proteases by Au(I) complexes: a kinetic and mechanistic investigation.” 2007. Doctoral Dissertation, University of Southern California. Accessed January 21, 2020. http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/529088/rec/3494.

MLA Handbook (7th Edition):

Gunatilleke, Shamila S. “Inhibition of cysteine proteases by Au(I) complexes: a kinetic and mechanistic investigation.” 2007. Web. 21 Jan 2020.

Vancouver:

Gunatilleke SS. Inhibition of cysteine proteases by Au(I) complexes: a kinetic and mechanistic investigation. [Internet] [Doctoral dissertation]. University of Southern California; 2007. [cited 2020 Jan 21]. Available from: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/529088/rec/3494.

Council of Science Editors:

Gunatilleke SS. Inhibition of cysteine proteases by Au(I) complexes: a kinetic and mechanistic investigation. [Doctoral Dissertation]. University of Southern California; 2007. Available from: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/529088/rec/3494


University of Southern California

3. Koenig, Stephanie A. The gold(I) mediated thiol/disulfide exchange reaction: a kinetic and mechanistic investigation.

Degree: MS, Chemistry, 2007, University of Southern California

Gold(I) complexes have been used to treat Rheumatoid Arthritis for decades, yet the precise biological targets of Au(I) remain unknown. Because Au(I) is thiophilic, biological thiols and disulfides are likely in vivo targets. In biochemistry, the thiol/disulfide exchange process is ubiquitous, crucial in maintaining cellular redox balance, protein structure and protein function. The ability of Au(I) to mediate the thiol/disulfide exchange reaction may be important to its biological reactivity. Gold(I) has been shown to mediate the thiol/disulfide exchange, but little is known about the kinetics or mechanism of the reaction. In this work, we have analyzed the kinetics and mechanism of the Au(I) promoted thiol/disulfide exchange reaction. Exchange reactions operate within a biologically relevant timeframe and are dependant on both Au(I) and disulfide concentrations. Evidence suggests some type of close interaction is occurring between the Au(I) and disulfide bond. We propose the reaction is operating via an oxidative-addition/reductive-elimination mechanism. Advisors/Committee Members: Barrios, Amy M. (Committee Chair), Reisler, Hanna (Committee Member), Haworth, Ian S. (Committee Member), Qin, Peter Z. (Committee Member), Periana, Roy A. (Committee Member).

Subjects/Keywords: gold; rheumatoid arthritis; thiol/disulfide exchange

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Koenig, S. A. (2007). The gold(I) mediated thiol/disulfide exchange reaction: a kinetic and mechanistic investigation. (Masters Thesis). University of Southern California. Retrieved from http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/535974/rec/6751

Chicago Manual of Style (16th Edition):

Koenig, Stephanie A. “The gold(I) mediated thiol/disulfide exchange reaction: a kinetic and mechanistic investigation.” 2007. Masters Thesis, University of Southern California. Accessed January 21, 2020. http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/535974/rec/6751.

MLA Handbook (7th Edition):

Koenig, Stephanie A. “The gold(I) mediated thiol/disulfide exchange reaction: a kinetic and mechanistic investigation.” 2007. Web. 21 Jan 2020.

Vancouver:

Koenig SA. The gold(I) mediated thiol/disulfide exchange reaction: a kinetic and mechanistic investigation. [Internet] [Masters thesis]. University of Southern California; 2007. [cited 2020 Jan 21]. Available from: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/535974/rec/6751.

Council of Science Editors:

Koenig SA. The gold(I) mediated thiol/disulfide exchange reaction: a kinetic and mechanistic investigation. [Masters Thesis]. University of Southern California; 2007. Available from: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/535974/rec/6751

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