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INHIBITION OF CYSTEINE PROTEASES BY Au(I) COMPLEXES:
A KINETIC AND MECHANISTIC INVESTIGATION
by
Shamila S. Gunatilleke
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(CHEMISTRY)
August 2007
Copyright 2007 Shamila S. Gunatilleke
Object Description
| Title | Inhibition of cysteine proteases by Au(I) complexes: a kinetic and mechanistic investigation |
| Author | Gunatilleke, Shamila S. |
| Author email | gunatill@usc.edu |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Chemistry |
| School | College of Letters, Arts and Sciences |
| Date defended/completed | 2007-06-13 |
| Date submitted | 2007 |
| Restricted until | Unrestricted |
| Date published | 2007-07-09 |
| Advisor (committee chair) | Barrios, Amy M. |
| Advisor (committee member) |
Thompson, Mark E. Baudry, Michel |
| Abstract | 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. |
| Keyword | gold complexes; enzyme inhibition; cathepsin; rheumatoid arthritis; proteases |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Type | texts |
| Legacy record ID | usctheses-m600 |
| Rights | Gunatilleke, Shamila S. |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | http://www.usc.edu/isd/libraries/services/ask_a_librarian/email/ |
| Filename | etd-Gunatilleke-20070709 |
| Archival file | uscthesesreloadpub_Volume29/etd-Gunatilleke-20070709-0.pdf |
Description
| Title | Page 1 |
| Full text | INHIBITION OF CYSTEINE PROTEASES BY Au(I) COMPLEXES: A KINETIC AND MECHANISTIC INVESTIGATION by Shamila S. Gunatilleke A Dissertation Presented to the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (CHEMISTRY) August 2007 Copyright 2007 Shamila S. Gunatilleke |
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