Publication Date

2015

Document Type

Dissertation/Thesis

First Advisor

Horn, James R.

Degree Name

Ph.D. (Doctor of Philosophy)

Legacy Department

Department of Chemistry and Biochemistry

LCSH

Biochemistry; Biophysics; Anti-infective agents--Research; Drug resistance in microorganisms--Research; Methionine--Research; Aminopeptidases--Research; Enzyme inhibitors--Structure-activity relationships--Research

Abstract

Methionine aminopeptidases are ubiquitous enzymes that are essential for the survival of numerous bacteria, removing N-terminal methionines from nascent proteins to initiate post-secondary modification. The ultimate goal of this study is to identify selective inhibitors targeting methionine aminopeptidases from infective organisms, including Burkholderia pseudomallei, Plasmodium falciparum, and Rickettsia prowazekii, to generate novel anti-infective agents.;Plasmodium falciparum methionine aminopeptidase ( PfMetAP2) was expressed and purified in-house from truncated sequence of PfMetAP2, while Burkholderia pseudomallei methionine aminopeptidase 1 and Rickettsia prowazekii methionine aminopeptidase 1 was obtained from Seattle Biomedical Research Institute. Our studies reveal the ability of nitroxoline analogs to inhibit both Burkholderia pseudomallei methionine aminopeptidase 1 and Plasmodium falciparum methionine aminopeptidase 2, as well as inhibiting cell growth of the target organisms. In addition, in vitro compound screening of 400 compounds with antimalarial activities was completed to identify potential lead compounds with IC50 of less than 10 microM against PfMetAP2. Finally, fluorescent plate-based assay studies were conducted to discover novel anti-Rickettsial therapeutics through the synthesis and design of inhibitors targeting Rickettsia prowazekii methionine aminopeptidase. Design and synthesis of analogs from active furan carboxylic acid and oxine series may lead to potential treatments for Rickettsia prowazekii.

Comments

Advisors: James R. Horn; Timothy J. Hagen.||Committee members: Gary M. Baker; R. Meganathan; Chong Zheng.

Extent

227 pages

Language

eng

Publisher

Northern Illinois University

Rights Statement

In Copyright

Rights Statement 2

NIU theses are protected by copyright. They may be viewed from Huskie Commons for any purpose, but reproduction or distribution in any format is prohibited without the written permission of the authors.

Media Type

Text

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