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dc.contributor.advisorTrawick, Mary Lynn.
dc.contributor.authorChen, Shen-En, 1981-
dc.contributor.otherBaylor University. Dept. of Chemistry and Biochemistry.en
dc.date.accessioned2008-06-11T16:43:58Z
dc.date.available2008-06-11T16:43:58Z
dc.date.copyright2008-05
dc.date.issued2008-06-11T16:43:58Z
dc.identifier.urihttp://hdl.handle.net/2104/5189
dc.descriptionIncludes bibliographical references (p. 361-367).en
dc.description.abstractγ-Glutamylamine cyclotransferase (γ-GACT) catalyzes cyclization of the L-glutamyl moiety in the isolated ε-(L-γ-glutamyl)-L-lysine crosslink, thereby releasing lysine. Although implicated in the degradation of the crosslink, the physiological function of γ-GACT has not been established, and purification and characterization of the enzyme is essential for the elucidation of its function. Although much information on the formation of this crosslink, which is essential in blood coagulation, wound healing, and apoptosis, has been reported in the literature, little has been documented about the degradation process. Design, synthesis, and development of potential inhibitors of γ-GACT are based on the previous substrate specificity studies, and the best inhibitor was incorporated into a solid support of a customized affinity column for enzyme purification. Although no X-ray crystal structures of the enzyme exist, molecular modeling of substrates and inhibitors may still provide useful information in the further development of inhibitors. Chagas’ disease, a result of Trypanosoma cruzi infection, is the third largest parasitic disease challenge after malaria and leishmania. It is an emerging concern since globalization brings the disease to the backyard of all countries. A significant percentage of all incidents develop into the chronic stage and lead ultimately to death caused by parasite induced organ failure. Currently, there is no satisfactory cure. Cruzipain, a cysteine protease essential to the T. cruzi organism, is a validated therapeutic target and its inhibition has been shown to achieve an experimental cure in mice. A library of thiosemicarbazone (TSC) and α,β-unsaturated carbonyl derivatives of benzophenone, propiophenone, α- and β-tetralone, 4-chromanone, and 4-thiochromenone was evaluated for inhibition of cruzain, a cloned version of cruzipain. Kinetics studies and molecular modeling was used to gain understanding of enzyme-inhibitor interactions. The best compounds, the TSC derivatives of a dibromobenzophenone and a bromo-α-tetralone were found to be slow, tight binding inhibitors of cruzain. Modeling studies support the kinetic results of a transient, reversible covalent bond formed between the inhibitor and the enzyme. These studies indicate that the best inhibitors from the library place the TSC moiety close to the active site thiolate and aromatic groups in the S2 pocket. Modeling studies also suggest that while the best inhibitors of cathepsin L from the same library have the TSC in the same position as in cruzain, the S1′ pocket, which is larger in cathepsin L than in cruzain, is more important in inhibitor binding. These studies are expected to help in the rational design of more potent inhibitors in the future.en
dc.description.statementofresponsibilityby Shen-En Chen.en
dc.format.extentxiii, 369 p. : ill.en
dc.format.extent1251577 bytes
dc.format.extent19701394 bytes
dc.format.mimetypeapplication/pdf
dc.format.mimetypeapplication/pdf
dc.language.isoen_USen
dc.rightsBaylor University theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. Contact librarywebmaster@baylor.edu for inquiries about permission.en
dc.subjectChagas' Disease -- Treatment.en
dc.subjectChemical inhibitors.en
dc.subjectTransglutaminases.en
dc.subjectEnzymes -- Purification.en
dc.titleModeling, design, and development of potential inhibitors of γ-glutamylamine cyclotransferase and inhibitors of cruzain as therapeutic agents for Chagas' disease.en
dc.typeThesisen
dc.description.degreePh.D.en
dc.rights.accessrightsWorldwide access.en
dc.rights.accessrightsAccess changed 5/24/11.
dc.contributor.departmentChemistry and Biochemistry.en


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