Improving the Biological Activity of Pyrrole-Imidazole Polyamides

• Main Author: Montgomery, David Church
• Format: Others
• Published: 2013
• Online Access: https://thesis.library.caltech.edu/7618/37/FULL%20THESIS-DCM.pdf; https://thesis.library.caltech.edu/7618/1/Cover-TOC.pdf; https://thesis.library.caltech.edu/7618/4/Chapter%201%20-%20Introduction.pdf; https://thesis.library.caltech.edu/7618/13/Chapter%202.pdf; https://thesis.library.caltech.edu/7618/19/Chapter%203.pdf; https://thesis.library.caltech.edu/7618/25/Chapter%204.pdf; https://thesis.library.caltech.edu/7618/31/Chapter%205.pdf; Montgomery, David Church (2013) Improving the Biological Activity of Pyrrole-Imidazole Polyamides. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/28SH-6Z27. https://resolver.caltech.edu/CaltechTHESIS:04182013-113509606 <https://resolver.caltech.edu/CaltechTHESIS:04182013-113509606>

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.