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Improving the biological activity of pyrrole-imidazole polyamides

Citation

Montgomery, David Church (2013) Improving the biological activity of pyrrole-imidazole polyamides. Dissertation (Ph.D.), California Institute of Technology. http://resolver.caltech.edu/CaltechTHESIS:04182013-113509606

Abstract

DNA is nature’s blueprint, holding within it the genetic code that defines the structure and function of an organism. A complex network of DNA-binding proteins called transcription factors can largely control the flow of information from DNA, so modulating the function of transcription factors is a promising approach for treating many diseases. Pyrrole-imidazole (Py-Im) polyamides are a class of DNA-binding oligomers, which can be synthetically programmed to bind a target sequence of DNA. Due to their unique shape complementarity and a series of favorable hydrogen bonding interactions that occur upon DNA-binding, Py-Im polyamides can bind to the minor groove of DNA with affinities comparable to transcription factors. Previous studies have demonstrated that these cell-permeable small molecules can enter cell nuclei and disrupt the transcription factor-DNA interface, thereby repressing transcription. As the use of Py-Im polyamides has significant potential as a type of modular therapeutic platform, the need for polyamides with extremely favorable biological properties and high potency will be essential. Described herein, a variety of studies have been performed aimed at improving the biological activity of Py-Im polyamides. To improve the biological potency and cellular uptake of these compounds, we have developed a next-generation class of polyamides bearing aryl-turn moieties, a simple structural modification that allows significant improvements in cellular uptake. This strategy was also applied to a panel of high-affinity cyclic Py-Im polyamides, again demonstrating the remarkable effect minor structural changes can have on biological activity. The solubility properties of Py-Im polyamides and use of formulating reagents with their treatment have also been examined. Finally, we describe the study of Py-Im polyamides as a potential artificial transcription factor.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:Bioorganic Chemistry; Molecular Recognition; Cancer Therapy; Drug Development
Degree Grantor:California Institute of Technology
Division:Chemistry and Chemical Engineering
Major Option:Chemistry
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Dervan, Peter B.
Thesis Committee:
  • Grubbs, Robert H. (chair)
  • Dervan, Peter B.
  • Campbell, Judith L.
  • Davis, Mark E.
Defense Date:11 March 2013
Funders:
Funding AgencyGrant Number
National Institutes of Health5T32GM007616
Record Number:CaltechTHESIS:04182013-113509606
Persistent URL:http://resolver.caltech.edu/CaltechTHESIS:04182013-113509606
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1093/nar/gkr970DOIUNSPECIFIED
http://dx.doi.org/10.1021/jo302053vDOIUNSPECIFIED
http://dx.doi.org/10.1021/jm300380aDOIUNSPECIFIED
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:7618
Collection:CaltechTHESIS
Deposited By: David Montgomery
Deposited On:25 Apr 2013 18:37
Last Modified:25 Apr 2013 18:37

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