Isoprenoid Biosynthesis Pathway as a Drug Target for Bisphosphonates: Transcriptional Profile Investigation
Leon-Rossell, Annette
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https://hdl.handle.net/2142/85459
Description
Title
Isoprenoid Biosynthesis Pathway as a Drug Target for Bisphosphonates: Transcriptional Profile Investigation
Author(s)
Leon-Rossell, Annette
Issue Date
2007
Doctoral Committee Chair(s)
Oldfield, Eric
Department of Study
Biophysics and Computational Biology
Discipline
Biophysics and Computational Biology
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
Biophysics, General
Language
eng
Abstract
Bisphosphonates are known as potent inhibitors of the enzyme farnesyl diphosphate synthase (FPPS) and are clinically used to treat bone related disorders such as osteoporosis and bone cancer. Here we describe the development, testing and study of the mechanism of action of novel bisphosphonates as anti-bacterial and anti-cancer agents. We identified a FPPS bisphosphonate inhibitor which in combination with the phosphonate drug fosmidomycin exerted a potent synergistic effect in Escherichia coli. Additionally, we designed novel groups of bisphosphonates which are ∼10-1000 fold more potent against tumor cell lines than conventional bisphosphonates due to their ability to inhibit more than one enzyme in the mevalonate pathway.
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