Author ORCID Identifier
https://orcid.org/0000-0003-0546-3138
Date of Award
8-13-2019
Degree Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Chemistry
First Advisor
W. David Wilson
Second Advisor
Gregory M. K. Poon
Third Advisor
Jenny J. Yang
Abstract
DNA-minor groove binding small molecules have been extensively developed to achieve higher binding affinity and specificity. Polyamides are a class of small molecules that can be programmed to target any predetermined DNA sequence. The development of hairpin polyamides along with introduction of β-alanine substituents, has greatly enhanced the DNA binding properties of these molecules. Yet the correlation between β-insert and binding properties remains unclear. On the other hand, the design of small-size, fluorescent hybrid polyamides has facilitated cell studies due to their ease of observation. There is a strong need to expand the DNA recognition sites of such molecules and extend their biological applications. This dissertation has explored the systematic design and synthesis of eight-ring hairpin polyamides as well as the modified Pyr-AzaHx hybrid polyamides. Comprehensive biophysical and biochemical tools were employed to evaluate their binding properties. The effects of β-alanine and N-terminal cationic groups on hairpin polyamides-DNA binding have been discussed. The binding properties of modified Pyr-AzaHx polyamides were explored. Altogether, the work provided fundamental guidance for the prediction of binding properties of similar molecules as well as strategies for the design of more competitive molecules.
Transcription factors bind to specific DNA sequences in the major groove and regulate gene expression. Abnormal expression of transcription factors is involved in the development of many serious diseases. Precise control of gene expression by targeting transcription factors can be an alternative therapeutic approach. Polyamides bind to DNA with affinities comparable to proteins, empowering them with the ability to interfere with transcription factors at specific DNA binding site and consequently altering the gene expression level. In this dissertation, the effect of polyamides on the binding of transcription factor PU.1 was studied. Abnormal expression of PU.1 is involved in the development of acute myeloid leukemia (AML). A positive correlation was established between eight-ring polyamide binding affinity and inhibition efficacy for PU.1. A non-inhibitor polyamide FH1024 was identified and the mechanism of action among polyamide, DNA and PU.1 was explored. The studies showed strong evidence of the capability of polyamides serving as drug agents. This work also established solid basis for the further cell studies.
DOI
https://doi.org/10.57709/15011814
Recommended Citation
Liu, Beibei, "DNA-binding Small Molecules as Drug Agents that Interfere with Transcription Factors: the Development, the Potential and the Future." Dissertation, Georgia State University, 2019.
doi: https://doi.org/10.57709/15011814
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