A number of well-known and well-investigated DNA binding drugs have been shown to induce bends in DNA. Studies on the biological affects of these agents have indicated that DNA bending by these agents plays an important role in their mechanism of action. Examination of the literature has suggested that there are at least four mechanisms by which DNA bending produces a biological affect. The four mechanisms are: 1. induction of DNA repair resulting in induced strand breakage; 2. facilitating DNA cleavage by binding to topoisomerases; 3. inhibit the binding of transcriptional proteins; 4. facilitating the binding of transcriptional proteins. In addition, the integral role that DNA bending plays in the regulation of gene expression indicates that DNA bending agents may be able to regulate the expression of disease-associated genes. Unfortunately, currently available agents are not sequence specific and therefore cannot be targeted to a specific region of the human genome. The creation of sequence specific DNA bending agents is hampered by the fact that the design principles for preparing DNA bending agents are non-existent in the chemical literature. To date, there has been only one example of a rationally designed DNA bending agent and this agent consisted of a triple helix making """"""""drug"""""""" delivery difficult. The purpose of this grant is to explore the design principles that would lead to the synthesis of a DNA bending agents. It is envisioned that this goal will provide utility in the creation of new medicinal agents that function by one of the five mechanisms outlined above. We will utilize the agents prepared in this proposal to investigate their ability to control transcription of simple model systems, as well as more complex systems related to angiogenesis. To accomplish this goal, we will leverage a combination of techniques from organic synthesis to molecular biology to focus on three specific aims.
Specific Aim I : The design, synthesis and evaluation of polyamide-based DNA bending agents that bind in a 1:1 complex with DNA;
Specific Aim II : Incorporation of DNA bending agents into polyamides that can target a specific gene in the human genome;
Specific Aim III : The design and synthesis of DNA bending agents that """"""""pull"""""""" the DNA together.
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